WO2020167706A1 - Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine - Google Patents

Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine Download PDF

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Publication number
WO2020167706A1
WO2020167706A1 PCT/US2020/017579 US2020017579W WO2020167706A1 WO 2020167706 A1 WO2020167706 A1 WO 2020167706A1 US 2020017579 W US2020017579 W US 2020017579W WO 2020167706 A1 WO2020167706 A1 WO 2020167706A1
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Prior art keywords
methyl
oxy
carboxylate
amino
pyrrolidine
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PCT/US2020/017579
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English (en)
Inventor
Stephane L. Bogen
Dane James CLAUSEN
Deodial Guy Guiadeen
Michael T. Rudd
Dexi YANG
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Merck Sharp & Dohme Corp.
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Priority to EP20709981.3A priority Critical patent/EP3924058A1/fr
Publication of WO2020167706A1 publication Critical patent/WO2020167706A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: orexin A (OX- A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al, Cell, 1998, 92, 573-585). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcolepsy, idiopathic hypersomnia, excessive daytime sleepiness, shift work disorder, obstructive sleep apnea and insomnia (Chemelli R.M. et al, Cell, 1999, 98, 437-451).
  • Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al, Cell, 1998, 92, 573-585). Orexins have also been indicated as playing a role in arousal, emotion, energy homeostasis, reward, learning and memory (Peyron, et al., Journal Neurosci., 1998,18(23):9996-100150, Harris, et al, Trends Neurosci., 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors (Sakurai T.
  • the orexin-1 receptor (OX or OX1R) is partially selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B with similar affinity.
  • OX1R the orexin-1 receptor
  • OX2 or OX2R the orexin-2 receptor
  • the present invention is directed to 5-alkyl pyrrolidine compounds which are agonists of orexin receptors.
  • the present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved.
  • the present invention is also directed to compositions comprising these compounds.
  • the present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
  • the present invention is directed to compounds of the formula I:
  • X is -O- or -NH-, or X may be a direct bond to Rl ;
  • Y is N or CH
  • Rl is selected from:
  • R2 is selected from:
  • heteroaryl is selected from: pyridyl, pyrimidinyl, and pyrazinyl, and the heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R4;
  • R2a and R2b are independently selected from:
  • R3 is selected from:
  • RlO and Rl 1 are independently selected from:
  • Ci-6alkyl which is unsubstituted or substituted with one to six R4;
  • R4 is selected from:
  • Ci-6alkyl which is unsubstituted or substituted with one to six fluoro
  • R5 and R6 are independently selected from:
  • R5 and R6 are joined together with the carbon atoms to which they are attached to form a -C3-6cycloalkyl ring, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R4;
  • An embodiment of the present invention includes compounds of the formula I: wherein:
  • X is -O- or -NH-, or X may be a direct bond to Rl ;
  • Y is N or CH
  • Rl is selected from:
  • R2 is selected from:
  • heteroaryl is selected from: pyridyl, pyrimidinyl, and pyrazinyl, and the heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R4;
  • R2a and R2b are independently selected from:
  • R3 is selected from:
  • RlO and Rl 1 are independently selected from:
  • Ci-6alkyl which is unsubstituted or substituted with one to six R4;
  • R4 is selected from:
  • Ci-6alkyl which is unsubstituted or substituted with one to six fluoro
  • R5 and R6 are independently selected from:
  • Ci-6alkyl where the alkyl is unsubstituted or substituted with one to six
  • R5 and R6 are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula lb’:
  • R5 and R6 are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula lb”:
  • R5 and R6 are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula lb”’:
  • R5 and R6 ar e defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Ic’:
  • R5 and R6 ar e defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Ic”:
  • R5 and R6 are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Ic”’:
  • Rl, R2, R3 and R5 are defined herein; or a pharmaceutically acceptable salt thereof.
  • R5 and R6 are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Id’:
  • R5 and R6 ar e defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Id”:
  • R5 and R6 are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Id”’:
  • Rl, R2, R3 and R5 are defined herein; or a pharmaceutically acceptable salt thereof.
  • R5 and R6 ar e defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Ie’:
  • R5 and R6 are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Ie”:
  • R5 and R6 are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds of the formula Ie”’:
  • Rl, R2, R3 and F are defined herein; or a pharmaceutically acceptable salt thereof.
  • An embodiment of the present invention includes compounds wherein X is -0-.
  • An embodiment of the present invention includes compounds wherein X is -NH-.
  • An embodiment of the present invention includes compounds wherein X is a direct bond to Rl.
  • An embodiment of the present invention includes compounds wherein Y is N.
  • An embodiment of the present invention includes compounds wherein Y is CH.
  • R2 is selected from:
  • phenyl which is unsubstituted or substituted with one to three fluoro, or -C i- 6alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro, and
  • R2 is selected from:
  • phenyl which is unsubstituted or substituted with -CF 3 , -CH2CF 3 , or one to three fluoro.
  • R2 is selected from:
  • An embodiment of the present invention includes compounds wherein R2a is hydrogen and R2b is hydrogen.
  • An embodiment of the present invention includes compounds wherein R2a is methyl and R2b is hydrogen.
  • An embodiment of the present invention includes compounds wherein R2a is methyl and R2b is methyl.
  • An embodiment of the present invention includes compounds wherein R2a is methyl and R2b is methyl, wherein R2a and R2b are attached to the same carbon atom.
  • An embodiment of the present invention includes compounds wherein R2a is fluoro and R2b is fluoro, wherein R2a and R2b are attached to the same carbon atom.
  • An embodiment of the present invention includes compounds wherein R2a is hydroxyl and R2b is hydrogen.
  • An embodiment of the present invention includes compounds wherein R2a is fluoro and R2b is hydrogen.
  • An embodiment of the present invention includes compounds wherein R3 is selected from: (1) -Ci-6alkyl, where the alkyl is unsubstituted or substituted with one to three fluoro,
  • R3 is selected from:
  • An embodiment of the present invention includes compounds wherein FP and R6 are independently selected from:
  • An embodiment of the present invention includes compounds wherein FP is methyl and R6 is hydrogen.
  • An embodiment of the present invention includes compounds wherein FP is ethyl and R6 is hydrogen.
  • An embodiment of the present invention includes compounds wherein R5 is ethyl and R6 is ethyl.
  • An embodiment of the present invention includes compounds wherein R and IIS are joined together with the carbon atoms to which they are attached to form a cyclopropyl ring.
  • Certain embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers,
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • Ci-6 as in Ci-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that Ci-6alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert- butyl, pentyl, and hexyl.
  • a group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
  • the present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Such compounds are identical to those disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2H and 3H, carbon such as HC, 13c and 14c, nitrogen such as 13N and l ⁇ N, oxygen such as 15o, l ⁇ O and 18(3, phosphorus such as 32p sulfur such as 35s, fluorine such as 1&F, iodine such as 123i and 125 [ nd chlorine such as 36ci.
  • Certain isotopically-labelled compounds of Formula I for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e.
  • substitutions with heavier isotopes such as deuterium, i.e. 2H. may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as HC, 1&F, 15(3 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • An embodiment of the present invention includes compounds that are substituted with a positron emitting isotope.
  • An embodiment of the present invention includes compounds that are substituted with a 1 lC isotope.
  • An embodiment of the present invention includes compounds that are substituted with an 18F isotope.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the invention.
  • different isotopic forms of hydrogen (H) include protium ( ⁇ ) and deuterium ( 2 H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for
  • Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the present invention.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates or solvates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particular embodiments include the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts. Salts of the compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Specific compounds within the present invention include a compound which is selected from the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual enantiomers or diastereomers thereof.
  • the present invention is also directed to the use of the compounds disclosed herein as agonists of orexin receptor activity.
  • the subject compounds and pharmaceutically acceptable salts thereof are useful in a method of agonizing orexin receptor activity in a subject such as a mammal comprising the administration of an amount of the compound.
  • a variety of other mammals may be administered with a compound of the present invention.
  • the present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof that could be useful in thereapy.
  • the present invention may further be directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for agonizing orexin receptor activity or treating the disorders and diseases noted herein in humans and animals.
  • a subject administered with a compound of the present invention, or a pharmaceutically acceptable salt thereof is generally a mammal, such as a human being, male or female.
  • the amount of compound administered to the subject is an amount sufficient to agonize the orexin receptor in the subject.
  • the amount of compound can be an “effective amount”, wherein the subject compound is administered in an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • An effective amount does not necessarily include considerations of toxicity and safety related to the administration of the compound.
  • treatment and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a subject that is predisposed to such disease or disorder.
  • administration of and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to to the subject.
  • compositions as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the utility of the compounds in accordance with the present invention as orexin receptor OX1R and/or OX2R agonists may be readily determined without undue experimentation by methodology well known in the art.
  • Both the OX1R and/or OX2R G-coupled protein receptors (GPCRs) couple through the Gaq signaling pathway, which ultimately promotes calcium mobilization via inositol triphosphate (IP3) production.
  • IP3 inositol triphosphate
  • IP-3 inositol triphosphate
  • IP-3 inositol triphosphate
  • IP-1 inositol monophosphate
  • the utility of the compounds in accordance with the present invention as orexin receptor OX1R and/or OX2R agonists may be determined utilizing this assay.
  • the OX1 and OX2 receptor agonist activity is determined in accordance with the following general experimental method.
  • Chinese hamster ovary (CHO) cells expressing human OX1R and/or the human OX2R were grown in Iscove’s modified DMEM containing glutaMAXTM, 1% G418, 100 U/mL penicillin, 100 pg/mL streptomycin and 10 % heat-inactivated qualified fetal bovine serum (FBS).
  • the OX2R cells were seeded at 10,000 cells/well/50 pL and the OX1R cells were seeded at 20,000 cells/well/50 pL into 384- well white tissue culture plates (Greiner; cat# 781080).
  • test compound stock 10 mM in DMSO
  • 100% DMSO acoustic liquid handler
  • IP-one detection reagents were prepared (38: 1 : 1 lysis buffer:D2:AB-cryptate reagents).
  • Six pL of mixed detection reagents were added to the cell plate using a Multidrop Combi (small cassette, Thermo Fisher Scientific cat #24073290) and incubated 60 minutes at room temperature in the dark. Fluorescence signal was detected using an Envision plate reader (Perkin Elmer) [LANCE/DELFIA Dual Enh (Em: APC 665; Ex: Cy5 620)].
  • Percent effect for each test compound was determined as the percentage of sample raw value/mean max effect, where the mean max effect was derived from the mean raw value of 32 control wells per assay plate (using Orexin A (cat# 003-30) at 1 pM for human OX1 R and a reference compound at 1 uM with 100% activity previously established by comparison to Orexin A for human OX2R).
  • the intrinsic orexin receptor agonist activity of a compound which may be used in the present invention may be determined by these assays.
  • the orexin receptors have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.
  • the compounds of the present invention could therefore potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy, narcolepsy syndrome accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, hypersomnia accompanied by daytime hypersomnia, interrupted sleep, sleep apnea, wakefulness, nocturnal myoclonus, disturbances of consciousness, such as coma, REM sleep interruptions, j et-lag, excessive daytime sleepiness, shift workers' sleep disturbance
  • the present invention may provide methods for: treating or controlling narcolepsy, narcolepsy syndrome accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, hypersomnia accompanied by daytime hypersomnia, interrupted sleep, sleep apnea, disturbances of consciousness, REM sleep interruptions, j et-lag, shift workers' sleep disturbances, dyssomnias, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment; treating or controlling sleep disturbances associated with diseases such as neurological disorders including neuropathic pain and restless leg syndrome; treating or controlling addiction disorders; treating or controlling psychoactive substance use and abuse; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling diabetes and appetite, taste, eating, or drinking disorders; treating or
  • EDS day
  • Parkinson's disease treating or controlling Guillain-Barre syndrome; treating or controlling Klein Levin syndrome; treating or controlling psychosis; treating or controlling dysthymic, mood, psychotic and anxiety disorders; treating side effects or complications due to anesthesia; reversal of anesthesia; reversal of anesthesia following surgery; treating or controlling depression, including major depression and major depression disorder; treating or controlling bipolar disorder; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian subject which comprises administering to the subject a compound of the present invention.
  • the compounds of the present invention may also potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of other disorders associated with orexin receptors, including one or more of the following conditions or diseases including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep;
  • obesity-related disorders overeating anorexia, bulimia, cachexia, dysregulated appetite control, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, lung disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischemic or haemorrhagic stroke;
  • craniopharyngioma the Prader-Willi Syndrome, Frohlich’s syndrome, GH-deficient subjects, normal variant short stature, Turner’s syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat- free mass, e.g, children with acute lymphoblastic leukemia, metabolic syndrome, also known as syndrome X, insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, hypogonadism in males and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, intestinal motility dyskinesias, obesity-related gastro-esophageal reflux, hypothalmic diseases, hypophysis diseases, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), breathlessness, cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gall
  • schizophrenia muscle-related disorders that are controlled by the excitation/relaxation rhythms imposed by the neural system such as cardiac rhythm and other disorders of the cardiovascular system; conditions related to proliferation of cells such as vasodilation or vasorestriction and blood pressure; cancer; cardiac arrhythmia; hypertension; congestive heart failure; conditions of the genital/urinary system; disorders of sexual function and fertility; adequacy of renal function; responsivity to anesthetics; mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to a general medical condition, and substance-induced mood disorders; affective neurosis; depressive neurosis; anxiety neurosis; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety
  • hypothalamic hypothyroidism hypothalamic hypothyroidism
  • hypothalamic- adrenal dysfunction idiopathic
  • hyperprolactinemia hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; amyotrophic lateral sclerosis; multiple sclerosis; ocular damage; retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, seizure disorders, absence seisures, complex partial and generalized seizures; Lennox-Gastaut syndrome; cognitive disorders including dementia (associated with Alzheimer’s disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson’s disease, Huntington’s disease, Pick’s disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline; schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizop
  • migraine including migraine headache
  • headache headache
  • hyperalgesia pain
  • pain such as hyperalgesia, causalgia, and allodynia; acute pain; bum pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g.
  • HIV post chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers; Kallman's syndrome (anosmia); asthma; cancer; conditions associated with visceral pain such as irritable bowel syndrome, and angina; eating disorders; urinary incontinence; substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, ***e, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorders); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage including ocular damage;
  • retinopathy macular degeneration of the eye; emesis; brain edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post- traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache and other diseases related to general orexin system dysfunction.
  • the subject compounds could further be of potential use in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the active ingredient may be administered to subjects (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the dose will vary from subject to subject depending upon the nature and severity of disease, the subject's weight, special diets then being followed by a subject, concurrent medication, and other factors which those skilled in the art will recognize.
  • dosage levels of between 0.0001 to 100 mg/kg. of body weight daily are administered to the subject, e.g., humans, adolescent humans and elderly humans, to obtain effective agonism of orexin receptors.
  • the dosage range will generally be about 0.5 mg to 10.0 g. per subject per day which may be administered in single or multiple doses.
  • the dosage range will be about 0.5 mg to 500 mg per subject per day; in another embodiment about 0.5 mg to 200 mg per subject per day; and in yet another embodiment about 5 mg to 50 mg per subject per day.
  • Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient.
  • the pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient.
  • the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
  • the compounds may be administered once or multiple times during the day.
  • the compounds may be administered upon awakeing or otherwise in the morning, or during waking hours. For example, the compounds may be administered about 1 hour after awakening, about 30 minutes after awakening or immediately after awakening.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated.
  • the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules.
  • the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000: 1 to about 1 :1000, such as about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction.
  • administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be administered in combination with compounds which are known in the art to be useful for treating or controlling narcolepsy, including e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, gamma- hydroxybutyric acid, sodium oxybate, or other oxybate salts, modafmil, armodafmil, caffeine, and salts thereof, and combinations thereof, and the like,
  • compounds which are known in the art to be useful for treating or controlling narcolepsy including e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, gamma- hydroxybutyric acid, sodium oxybate, or other oxybate salts, modafmil, armodafmil, caffeine, and salts thereof, and combinations thereof, and the like,
  • the compounds of the present invention may be administered in combination with compounds which are known in the art to be useful for preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, orexin antagonists, other orexin agonists, prokineticin agonists and antagonists,
  • compounds which are known in the art to be useful for preventing and treating sleep disorders and sleep disturbances including e.g., sedatives, hypnotics, anxiolytics, antipsych
  • pyrazolopyrimidines T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafmil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014
  • mephobarbital meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafmil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, omortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, trice
  • the subject compound may be employed in combination with other compounds which are known in the art, either administered separately or in the same pharmaceutical compositions, including, but are not limited to: insulin sensitizers including (i) PPARy antagonists such as glitazones (e.g.
  • ciglitazone darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, and the like);
  • biguanides such as metformin and phenformin
  • insulin or insulin mimetics such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7) (insulintropin); and GLP-1 (7-36)-NH2)
  • sulfonylureas such as acetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide; glyburide
  • glipentide gliquidone; glisolamide; tolazamide; and tolbutamide;
  • a-glucosidase inhibitors such as acarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q;
  • salbostatin CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the like;
  • cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and other statins),
  • bile acid absorbers/sequestrants such as cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®; LoCholest®, and the like,
  • proliferator-activater receptor a agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate
  • WO 96/33159 WO 98/33765, W098/43636, W098/43635, WO 01/09120, W098/31227, W098/41519, WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, W002/076949, WO 03/007887, WO 04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5) P3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085,
  • WO 01/77094 (7) neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY- 357897, CP-671906, GI-264879A, and those disclosed in U.S. Patent No. 6,001,836, and PCT Patent Publication Nos.
  • WO 96/14307 WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528;
  • neuropeptide Y5 antagonists such as GW- 569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, and those disclosed in U.S. Patent Nos. 6,057,335; 6,043,246; 6,140,354; 6,166,038;
  • MCH melanin-concentrating hormone
  • MCH1R melanin-concentrating hormone 1 receptor
  • melanocortin agonists such as Melanotan II
  • Mc4r melanocortin 4 receptor
  • CHIR86036 Choiron
  • ME-10142 ME-10142
  • ME-10145 Melacure
  • CHIR86036 Choiron
  • PT-141 PT-14
  • 5HT-2 5HT-2 agonists
  • 5HT2C serrotonin receptor 2C
  • BVT933, DPCA37215, WAY161503, R-1065 and those disclosed in U.S. Patent No. 3,914,250, and PCT Application Nos.
  • WO 02/36596 WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19) CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and those discribed in U.S. Patent No.
  • GLP-1 agonists (21) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3- (lH-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and 0-[3-(lH-imidazol-4-yl)propanol]-carbamates; (25) b-hydroxy steroid dehydrogenase- 1 inhibitors (b-HSD-l); (26) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast;
  • PDE phosphodieste
  • leptin including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives; (32) BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6,beta-Alal l,Phel3,Nlel4]Bn(6-14) and [D- Phe6,Phel3]Bn(6-13)propylamide, and those compounds disclosed in Pept. Sci.
  • CNTF Central neurotrophic factors
  • GI-181771 Gaxo-SmithKline
  • SR146131 Sanofi Synthelabo
  • butabindide PD 170,292, and PD 149164 (Pfizer)
  • CNTF derivatives such as axokine (Regeneron);
  • monoamine reuptake inhibitors such as sibutramine;
  • UCP-1 uncoupling protein-1
  • activators such as phytanic acid, 4-[(E)- 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-l-propenyl]benzoic acid (TTNPB), retinoic acid;
  • thyroid hormone b agonists such as KB-2611 (KaroBioBMS
  • FAS fatty acid synthase inhibitors, such as Cerulenin and C75
  • acyltransferase 1 inhibitors (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoid antagonists; (43) acyl- estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M.
  • dipeptidyl peptidase IV (DP-IV) inhibitors such as isoleucine thiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011,
  • Topiramate (Topimax®); (50) peptide YY, PYY 3-36, peptide YY analogs, derivatives, and fragments such as BIM-43073D, BIM-43004C (Olitvak, D.A. et al, Dig. Dis. Sci.
  • Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY;
  • Neuropeptide Y4 (NPY4) agonists such as pancreatic peptide (PP), and other Y4 agonists such as 1229U91;
  • cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522, ABT963, CS502 and GW406381;
  • NPY2 (NPY2) receptor agonists such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and cyclo-(28/32)
  • Neuropeptide Y1 (NPY1) antagonists such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56) Opioid antagonists such as nalmefene (Revex ®), 3- methoxynaltrexone, naloxone, naltrexone; (57) 11 b HSD-1 (11 -beta hydroxy steroid
  • dehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and those disclosed in WO 01/90091, WO 01/90090, WO 01/90092, US 6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60) amphetamine; (61) benzphetamine; (62) chlorphentermine; (63) clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67) cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex; (74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77) levamfetamine; (78) levophacetoperane; (
  • the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, a -adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HTIA agonists or antagonists, especially 5-HTIA partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • norepinephrine reuptake inhibitors including tertiary amine tricyclics and secondary amine tricyclics
  • Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline: citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
  • the subject compound may be employed in combination with anti-Alzheimer's agents; beta-secretase inhibitors, such as verubecestat; gamma-secretase inhibitors; growth hormone secretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors; NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonists or CB-1 receptor inverse agonists; antibiotics such as doxycy cline and rifampin; N- methyl-D-aspartate (NMD A) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPA agonists; PDE IV inhibitors; GABAA inverse agonist
  • the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate
  • the subject compound may be employed in combination with acetophenazine, alentemol, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene or trifluoperazine.
  • the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine,
  • butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the subject compound may be employed in combination with a nicotine agonist or a nicotine receptor partial agonist such as varenicline, opioid antagonists (e.g., naltrexone (including naltrexone depot), antabuse, and nalmefene),
  • a nicotine agonist or a nicotine receptor partial agonist such as varenicline, opioid antagonists (e.g., naltrexone (including naltrexone depot), antabuse, and nalmefene)
  • opioid antagonists e.g., naltrexone (including naltrexone depot), antabuse, and nalmefene
  • dopaminergic agents e.g., apomorphine
  • ADD/ ADHD agents e.g., methylphenidate hydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g., Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g., Adderall®)) and anti-obesity agents, such as apo- B/MTP inhibitors, 11 Beta-hydroxy steroid dehydrogenase- 1 (UBeta-HSD type 1) inhibitors, peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, b3 adrenergic receptor agonists, dopamine receptor agonists, melanocyte-stimulating hormone receptor analogs, 5-HT2c receptor agonists, melanin concentrating hormone receptor antagonists, leptin, le
  • glucocorticoid receptor antagonists such as suvorexant, other orexin agonists, glucagon-like peptide- 1 receptor agonists, ciliary neurotrophic factors, human agouti-related protein antagonists, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists, and pharmaceutically acceptable salts thereof.
  • the subject compound may be employed in combination with an agent such as aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,
  • an agent such as aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,
  • phenylpropanolamine phenylpropanolamine, picilorex and sibutramine
  • selective serotonin reuptake inhibitor SSRI
  • halogenated amphetamine derivatives including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine
  • pharmaceutically acceptable salts thereof include
  • the subject compound may be employed in combination with an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin- 1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.
  • a lipoxygenase inhibitor such as an inhibitor of 5-lip
  • the subject compound may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline,
  • a pain reliever such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline,
  • xylometazoline propylhexedrine, or levo-desoxy-ephedrine
  • an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan
  • a diuretic a sedating or non-sedating antihistamine.
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention may be effective
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Oily suspensions may be formulated by suspending the active ingredient in a suitable oil.
  • Oil-in-water emulsions may also be employed.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed.
  • the compounds of the present invention may also be formulated for administered by inhalation.
  • the compounds of the present invention may also be administered by a transdermal patch by methods known in the art.
  • TFA trifluoracetic acid
  • X-Phos 2-(dicyclohexyl-phosphino)-2',4',6'- triisopropylbiphenyl.
  • the compounds of the present invention can be prepared in a variety of fashions.
  • the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
  • Step 1 methyl (i?)-5-(((benzyloxy)carbonyl)amino)-3-oxohexanoate (B-l)7
  • Step 4 benzyl (4aR,6R,7aS)-l-(4-methoxybenzyl)-6-methylhexahydro-5H-pyrroloi3,2- dll 1,2,31 oxathiazine-5-carboxylate 2,2-dioxide (B)
  • Step 1 benzyl (2j?.3 ⁇ .5j?)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxybenzyl)ainino)-5- methylpyrrolidine-l-carboxylate (C-1)
  • Step 2 (2j?.3A5j?)-2-((4-isopropylphenoxy)methyl)-/V-(4-methoxybenzyl)-5-methylpyrrolidin-3- amine
  • Step 1 benzyl (2i?,3S',5i?)-2-((4-(trifluoromethyl)phenoxy)methyl)-3-((4-methoxybenzyl)amino)-
  • Step 1 benzyl (2R,3S,5R)-2-((4-(2,2,2-trifluoroethyl)phenoxy)methyl)-3-((4-methoxybenzyl)- arnino)-5-methylpyrrolidine-l -carboxylate (E-1)
  • reaction mixture was filtered through a pad of diatomaceous earth. The organic phase was collected, concentrated and dissolved in 30 mL of THF, then was cooled to 0°C. 5 mL of 2N HCI was added and the reaction mixture, then the reaction was stirred for 20 min, LC-MS showed only the desired product. The reaction mixture was diluted with 50 mL of EtOAc, then to the reaction mixture was added K2CO3 to neutralized the reaction mixture.
  • Stepl 1-benzyl 2-methyl (5//)-3-hvdro ⁇ v-5-melhyl pyrrolidine- 1.2-dicarbo ⁇ late (F-l )
  • Step 3 benzyl (5i?)-3-(benzyloxy)-2-(hvdroxymethyl)-5-methylpyrrolidine-l-carboxylate (F-3)
  • Step 1 1-benzyl 3-ethyl 4-oxo-5-((((ls.4s)-4-phenylcvclohexyl)oxy)methyl)pyrrolidine-1.3- dicarboxylate (C-2)
  • Step 2 benzyl 3-oxo-2-((( 4-phenylcvclohexyl)oxy)methyl)pyrrolidine-l-carboxylate (1-3)
  • Step 1 benzyl (C/A)-3-(methylsulfonamido)-2-((((C/A)-4-phenylcvclohexyl)oxy)methyl)- pyrrolidine-l-carboxylate (J-l)
  • Step 2 N-((CAS)-2-((((CAS)-4-phenylcvclohexyl)oxy)methyl)pyrrolidin-3-yl)methanesulfonamide
  • Step 1 N-((C/M-l-benzyl-2-((( -phenylcvclohexyl)oxy)methyl)pynOlidin-3-
  • Step 2 N-((C/S , )-l-benzyl-5-oxo-2-((((C/S , )-4-phenylcyclohexyl)oxy)methyl)pyrrolidin-3- vDmethanesulfonamide (INTERMEDIATE K)
  • Step 1 8-(3-nuorophen ⁇ l)- 1.4-dioxaspirol4.5 ldec-7-ene 1 L-l )
  • Step 3 4-(3-fluoronhenyl)cvclohexan-l-one (L-3)
  • Each the intermediate compounds were prepared by following the same procedure as intermediate H using commercially available 2-bromo-l,4-difluorobenzene, l-bromo-2,3,5- trifluorobenzene and 1 -bromo-2-(trifluoromethyl)benzene and 1 -bromo-2-fluorobenzene.
  • Step 1 1 -benzyl 2-methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5- methylpyrrolidine-1.2-dicarboxylate (R-1
  • Benzyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2- (((triethylsilyl)oxy)methyl)pyrrolidine-l-carboxylate (S) and benzyl (2R,3S,5R)-5-methyl-2- (((triethylsilyl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrobdine-l- carboxylate (T) were prepared according to the same procedure provided in Intermediate R by substituting the appropriate methylsulfonyl chloride or trifluoroacetic anhydride.
  • Step 2 benzyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-2-((((CIS)-4- phenylcvclohexyl)oxy)methyl)pyrrolidine-l -carboxylate (U-2)
  • Step 3 N-(4-methoxybenzyl)-N-((CIS)-2-((((CIS)-4-phenylcvclohexyl)oxy)methyl)pyrrolidin-3- vDmethanesulfonamide (U-3)
  • Step 4 tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-2-((((CIS)-4- phenylcvclohexyl)oxy)methyl)pyrrolidine-l -carboxylate (U-4)
  • N-(4-methoxybenzyl)-N-((CIS)-2-((((CIS)-4- phenylcyclohexyl)oxy)methyl)pynOlidin-3-yl)methanesulfonamide (U-3) (1.90 g, 4.02 mmol) in DCM (20.10 ml) at ambient temperature was added BOC20 (1.120 ml, 4.82 mmol) and TRIETHYLAMINE (1.121 ml, 8.04 mmol).
  • Step 5 tert-butyl (CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-oxo-2-((((CIS)-4- phenylcvclohexyl)oxy)methyl)pyrrolidine-l -carboxylate (INTERMEDIATE U)
  • Step 1 tert-butyl (S)-3-amino-4-((tert-butyldiphenylsilyl)oxy)butanoate (V-2)
  • Step 7 dimethyl (2R.3S.5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-((4- methoxybenzyl)amino)pyrrolidine- 1.2-dicarboxylate (V-8)
  • Step 8 dimethyl (2R.3S.5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-((N.N- dimethylsulfamoyl)(4-methoxybenzyl)amino)pyrrolidine-1.2-dicarboxylate (INTERMEDIATE Y)
  • Step 1 benzyl (2R.3S.5R)-2-(((4-(3-fluorophenyl)cvclohexyl)oxy)methvD-5-methyl-3-(2.2.2- trifluoro-N-(4-methoxybenzyl)acetamido)pynOlidine-l-carboxylate tW'-l )
  • TMS-OTf Trimethylsilyl trifluoromethanesulfonate
  • Step 4 methyl (2R,3S,5R)-2-((((ls,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-3-((4- methoxybenzyl)amino)-5-methylpyrrolidine- 1 -carboxylate (W-4)
  • W-3 methyl (2R,3S,5R)-2-(((4-(3- fluorophenyl)cyclohexyl)oxy)methyl)-5-methyl-3-(2,2,2-trifluoro-N-(4- methoxybenzyl)acetamido)pyrrolidine-l-carboxylate (W-3) (353 mg, 0.608 mmol) in THF (4000 pi)/ MeOH (2000 pl)/H20 (2000 m ⁇ ) was added LiOH (87 mg, 3.65 mmol).
  • Step 5 methyl (2R.3S.5R)-3-amino-2-((((ls.4S)-4-(3-fluorophenyl)cvclohexyl)oxy)methyl)-5- methylpyrrolidine-l-carboxylate (INTERMEDIATE W)
  • Step 1 Methyl (2R.3S.5R)-2-(((4-(benzyloxy)cvclohexyl)oxy)methyl)-3-((N.N- dimethylsuiramoyl )(4-metho ⁇ vbenzyl )amino)-5-methyl pyrrolidine- 1 -carbowlate (X-l )
  • Step 2 Methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(((4- hvdroxycvclohexyl)oxy)methyl)-5-methylpyrrolidine- 1 -carboxylate (X-2)
  • Step 3 Methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2- (((4-oxocvclohexyl)oxy)methyl)pyirolidine-l-carboxylate tX-3)
  • Step 3 Methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2- (((4-(((trifluoromethyl)sulfonyl)oxy)cvclohex-3-en-l-yl)oxy)methyl)pyrrolidine-l-carboxylate
  • POTASSIUM BIS(TRIMETHYLSILYL)AMIDE (2145 m ⁇ , 2.145 mmol) (1 M in THF) was then added via a Hamilton syringe and needle dropwise and the mixture stirred at -78 °C for 2 h. At -78 °C the reaction was quenched with Sat. Aq.
  • Step 1 benzyl (2R.3S.5R)-2-((4-isopropylphenoxy)melhyl )-3-(N-(4-melhoxybenzyl )- melhylsulfonamido)-5-melhylpyrrolidine- 1 -carboxylale ( 1-1)
  • Step 2 /V-((2j?.3ri , .5j?)-2-((4-isopropylphenoxy)methyl)-5-methylpyrrolidin-3-yl)methane- sulfonamide (1-2)
  • Step 3 (2/C3ri'.5/ )-yV-elhyl-2-(((4-isopropylcvclohexyl)oxy)melhyl )-5-melhyl-3- (methylsulfonamido)pyrrolidine-l -carboxamide ( 1)
  • Step 1 (2j?.3X5j?)-/V-ethyl-3-((4-methoxybenzyl)amino)-5-methyl-2-((4-(trifluoromethyl)phe noxy)methyl)pyrrolidine-l -carboxamide (2-1)
  • Step 2 (2i?.3.S'.5iO-3-arnino-7V-ethyl-5-rnethyl-2-((4-(trifluoromethyl)phenoxy)methvD- pyrrobdine-l-carboxamide (2-2)
  • reaction mixture was filtered through a pad of diatomaceous earth.
  • the filtrate was neutralized with TEA, then was concentrated in vacuo and the residue was purified by prep silica gel TLC with 5% 7N NEb in MeOH/DCM to provide the title compound (2/L35'.5//)-3-amino- iV-ethyl-5-methyl-2-((4-(tririuoromethyl)phenoxy)methyl)pyrrolidine- 1 -carboxamide (2-2).
  • LC- MS 346.2 (M+l).
  • Step 3 (2iL3£5i?)-A-ethyl-5-methyl-3-(methylsulfonamido)-2-((4-(trifluoromethyl)phenoxy)- methyl)pyrrolidine-l -carboxamide (2-3)
  • Step 4 (2iL3£5i?)-A-ethyl-5-methyl-3-(methylsulfonamido)-2-(((4-(trifluoromethyl)cvclohexyl)- oxy)methyl)pyrrolidine- 1 -carboxamide (2)
  • Step 1 methyl (2j?.3X5j?)-2-((4-isopropylphenoxy)methyl)-3-((4-methoxybenzyl)amino)-5- methylpyrrolidine-l -carboxylate (3-1)
  • Step 2 methyl (2j?.3X5j?)-3-amino-2-((4-isopropylphenoxy)methyl)-5-methylpyrrolidine-l- carboxylate (3-2)
  • Step 3 methyl (2iC3£.5i?y2-((4-isopropylphenoxylmethyll-5-methyl-3-(methylsulfonamidol- pyrrolidine-l-carboxylate (3-31
  • Step 4 EXAMPLE 3: methyl (2/C3ri'.5/ )-2-(((4-isopropylcvclohexyl)oxy)melhyl)-5-melhyl-3- (methylsulfonamido/pyrrolidine-l-carboxylate and EXAMPLE 4: methyl (2R 3S 5R)-2- ((((ls.4M-4-isopropylcvclohexyl)oxy)methyl)-5-methyl-3-(methylsulfonamido)pyrrolidine-l- carboxylate
  • the following compounds were prepared according to the general procedure provided in Examples 1-4, and procedures herein, by substituting the appropriate alkyl carbonochloridate and sulfamoyl chloride.
  • the starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.
  • Step 1 benzyl (2£5i ⁇ !-3-(benzyloxy)-5-methyl-2-((((ls.4i ⁇ !-4-phenylcvclohexyl)oxy)methyl)- pyrrobdine-1 -carboxylate (15-1)
  • Step 2 methyl (26'.5//)-3-(benzylo ⁇ v)-5-methyl-2-(((( 1 S.4//)-4-phenylcvclohe ⁇ yl )o ⁇ v)melhyl )- pyrrolidine-1 -carboxylate (15-2)
  • Step 5 methyl (2R,3S,5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-((((ls,4S)-4-
  • Step 7 methyl (2/C3ri'.5/ )-5-melhyl-3-(melhylsulfonamido)-2-(((( 1 s.4 ⁇ S)-4-phenylcvclohexyl)-
  • Step 1 2.2-difluoroethyl (2£5i ⁇ !)-3-(benzyloxy)-5-methyl-2-((((l.s'.4i ⁇ !-4-phenylcvclohexyl)oxy)- methyl ipyrrol idine- 1 -carboxylale (16-11
  • Step 5 2.2-difluoroethyl (2R.3S.5R)-3-amino-5-methyl-2-((((ls.4S)-4-phenylcvclohexyl)oxy)- methvDpyrrolidine- 1 -carboxylate ( 16-5)
  • Step 6 2.2-difluoroethyl (2R.3S.5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-((((ls.4S)-4- phenylcvclohexyl)oxy)methyl)pyrrolidine-l -carboxylate ( 16)
  • the following compounds were prepared according to the general procedure provided in Examples 1-15, and procedures herein, by substituting the appropriate alkyl carbonochloridate, methylsulfamoyl chloride and dimethylsulfamoyl chloride.
  • the starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.
  • Step 1 benzyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)amino)-2-((((lR.4S)-2-fluoro-4- phenylcvclohexyl)oxy)methyl)-5-methylpyrrolidine-l-carboxylate (30-1)
  • Step 3 methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)amino)-2-((((lR.4S)-2-fluoro-4- phenylcvclohexyl)oxy)methyl)-5-methylnyrrolidine-l-carboxylate (30)
  • the following compounds were prepared according to the general procedure provided in Examples 30, and procedures herein, by using different arylcyclohexanones.
  • the starting materials are either prepared as described in the intermediates section (intermediate Q), or commercially available 4-(3,5-difluorophenyl)cyclohexan-l-one as described in Example 32.
  • Step 1 benzyl (2R.3S.5R)-2-(((2-methoxy-4-phenylcvclohexyl)oxy)methyl)-3-(N-(4-methox vbenzyl)methylsulfonamido)-5-methylpyrrobdine-l-carboxylate (33-1)
  • Step 2 N-((2R.3S.5R)-2-(((2-methoxy-4-phenylcyclohexyl)oxy)methyl)-5-methylpyrrobdin-3- yl)-N-(4-methoxybenzyl)methanesulfonamide (33-21
  • Step 3 methyl (2R.3S.5R)-2-(((2-methoxy-4-phenylcvclohexyl)oxy)methyl)-3-(N-(4- methoxybenzyl)methylsulfonamido)-5-methylpyrrolidine-l-carboxylate (33-31
  • Step 4 methyl (2R.3S.5R)-2-(((2-methoxy-4-phenylcvclohexyl)oxy)methyl)-5-methyl-3- (methylsulfonamido)pyrrolidine- 1 -carboxylate (331
  • Step 1 N-(4-methoxybenzyl)-N-((2R.3S.5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)pynOlidin- 3-yl jmelhanesul Ton amide (34-1)
  • Step 3 methyl (2R,3S,5R)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-methyl-2-(((2-methyl-
  • Trimethylsilyl trifluoromethanesulfonate (0.040 ml, 0.220 mmol) was added. The reaction mxiture was allowed warm up to 0°C slowly. After 1.5 hrs stirring at 0°C, LC-MS showed the major was desired product formation. The reaction mixture was quenched with sat. aq. NaHCC ⁇ . The reaction mixture was extracted by 2 portions of 10 ml of DCM. The combined organic phase was collected and concentrated to leave colorless oil.
  • Step 4 methyl (2R.3S.5R)-5-methyl-2-(((2-methyl-4-phenylcvclohexyl)oxy)methyl)-3-
  • Step 1 N-(4-methoxybenzyl)-N-((2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)pynOlidin-
  • Step 2 methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2-
  • Step 3 methyl (2R,3S,5R)-2-(((4-(benzyloxy)cyclohexyl)oxy)methyl)-3-((N,N-dimethyl- sulfamoyl)(4-methoxybenzyl)amino)-5-methylpynOlidine-l-carboxylate (36-3)
  • methyl (2R,3S,5R)-3-((N,N-dimethylsulfamoyl)(4- methoxybenzyl)amino)-5-methyl-2-(((triethylsilyl)oxy)methyl)pyrrolidine- 1 -carboxylate (36-2) (3.32 g, 6.27 mmol) in Acetonitrile (48 ml) at 0°C was added 4-(benzyloxy)cyclohexan-l-one (1.92 g, 9.40 mmol) followed by triisopropylsilane (2.57 ml, 12.53
  • reaction mixture was cooled to -30 °C, trimethylsilyl trifluoromethanesulfonate (1.134 ml, 6.27 mmol) was added. It was continued to stir at -30°C for 4 hrs. LC-MS showed almost completion. The reaction mixture was quenched with sat. aq. NaHCC ⁇ . The reaction mixture was extracted by 2 portions of 10 ml of DCM. The combined organic phase was collected and concentrated to leave yellow oil.
  • Step 4 methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-(((4-h vdroxycvclohexyl)oxy)methyl)-5-methylpyrrolidine-l-carboxylate (36-41
  • Step 5 methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2- (((4-oxocvclohexyl)oxy)methyl)pyrrolidine-l-carboxylate (36-5)
  • reaction mixture was stirried at 0°C for 30 mins and then let it warm up to rt slowly and stirred at rt overnight. LC-MS showed completion. The reaction mixture was washed with sat. NaHC03. The organic layer was dried with MgS04, concentrated to leave yellow oil.
  • Step 6 methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2- ((((S)-4-(((trifluoromethyl)sulfonyl)oxy)cvclohex-3-en-l-yl)oxy)methyl)pyrrolidine-l- carboxylate (36-6)
  • Step 7 methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((S)-3'- fluoro-2.3.4.5-tetrahvdro- biphenyll-4-yl)oxy)methyl)-5-methylpyrrolidine-l-carboxylate
  • Step 8 methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)amino)-2-((((S)-3'-fluoro-2.3.4.
  • Step 9 methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((lS)-4- (3-fluorophenyl)-3-hvdroxycvclohexyl)oxy)methyl)-5-methylpyrrolidine-l -carboxylate (36-8)
  • Step 10 methyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)amino)-2-((((lS)-4-(3-fluorophenyl)-3- hv droxycv cl ohexyl)oxy)methyl)-5-methylpyrrolidine-l -carboxylate (361
  • Step 1 benzyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((ls.4S)-4- (3-fluorophenyl)cvclohexyl)oxy)methyl)-5-methylpyrrolidine-l-carboxylate (37-1)
  • Step 1 2.2.2-trifluoro-N-(4-methoxybenzyl)-N-((2R.3S.5R)-5-methyl-2- (((lrielhylsilyl)oxy)melhyl)pyrrolidin-3-yl (acetamide (38-1)
  • Step 2 isopropyl (2R,3S,5R)-5-methyl-2-(((triethylsilyl)oxy)methyl)-3-(2,2,2-trifluoro-N-(4- methoxybenzyl)acetamido)pyrrolidine-l -carboxylate (38-2)
  • Step 3 benzyl 4-(((2R,3S,5R)-l-(isopropoxycarbonyl)-5-methyl-3-(2,2,2-trifluoro-N-(4-
  • Step 5 isopropyl (2R.3S.5R)-5-methyl-2-(((l-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3- (2.2.2-trifluoro-N-(4-methoxybenzyl)acetamido)pyrrohdine-l-carboxylate (38-5)
  • Step 6 isopropyl (2R.3S.5R)-3-((4-methoxybenzyl)amino)-5-methyl-2-(((l-(pyrimidin-2- yl)piperidin-4-yl)oxy)methyl)pyrrolidine-l-carboxylate (38-6)
  • Step 7 isopropyl (2R.3S.5R)-3-((4-methoxybenzyl)(N-methylsulfamoyl)amino)-5-methyl-2-(((l- (pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)pyrrolidine-l -carboxylate (38-7)
  • Step 8 isopropyl (2R.3S.5R)-5-methyl-3-((N-methylsulfamoyl)amino)-2-(((l-(pyrimidin-2- yl)piperidin-4-yl)oxy)methyl)pyrrolidine- 1-carboxylate (38)
  • Step 1 isopropyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2- (((triethylsilyl)oxy)methyl)pyrrolidine-l -carboxylate (39- It
  • Step 2 benzyl 4-(((2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-l- (isopropoxycarbonyl)-5-methylpyrrolidin-2-yl)methoxy)piperidine-l-carboxylate (39-3)
  • Step 3 isopropyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-methyl-2- ((piperidin-4-yloxy)methyl)pyrrolidine-l-carboxylate (39-4)
  • benzyl 4-(((2R,3S,5R)-3-((N,N-dimethylsulfamoyl)amino)-l- (isopropoxy-carbonyl)-5-methylpynOlidin-2-yl)methoxy)piperidine-l-carboxylate (39-3) 13 mg, 0.024 mmol
  • THF 1.0 ml
  • 10% palladium on carbon 3.84 mg, 3.61 pmol
  • Step 4 isopropyl (2R.3S.5R)-3-((N.N-dimethylsulfamoyl)amino)-2-(((l-(5-fluoropyrimidin-2- yl)piperidin-4-yl)oxy)methyl)-5-methylpyrrolidine-l-carboxylate (391
  • Step 1 N-((C/S)-l-benzyl-5-ethyl-2-((((C/S)-4-phenylcyclohexyl)oxy)methynpyrrolidin-3- vnmethanesulfonamide (40-1) and N-ri( 75V4-ben/yl-5-llri( 'AV)-4- phenylcvclohexyl)oxy)melhyl )-4-azaspirol2.4lheplan-6-yl )melhanesulfonamide (41-1)
  • Tetrahydrofuran (2190 pi) at -78 °C was added titanium(IV) isopropoxide (289 m ⁇ , 0.986 mmol). After stirring for 10 min, add ethylmagnesium bromide (657 m ⁇ , 1.971 mmol). The mixture was stirred for 30 min before warming to ambient temperature. After 1 hour at ambient temperature was added titanium(IV) isopropoxide (289 m ⁇ , 0.986 mmol) followed by ethylmagnesium bromide (657 m ⁇ , 1.971 mmol). After another 2 hours added ethylmagnesium bromide (657 m ⁇ , 1.971 mmol).
  • Step 2 N-((C/X)-5-ethyl-2-((((C/X)-4-phenylcvclohexyl)oxy)methyl)pyrrolidin-3- vDmethanesulfonamide (40-2) and N-((C/X)-5-((((C/X)-4-phenylcvclohexyl)oxy)methyl)-4- azaspirol2.41heptan-6-yl)methanesulfonamide (41-2)
  • Step 3 methyl (C/A)-5-ethyl-3-(methylsulfonamido)-2-((((C/A)-4-phenylcvclohexyl)oxy)- methvDpyrrolidine- 1 -carboxylate (40)
  • Step 1 N-ttCAV)- 1 -benzyl-5-oxo-2-(((Y7V)-4-phenylcvclohexyl)oxy)melhyl)pyrrolidin-3-yl)-N- ((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42-1)
  • Step 2 N-((CIS)-l-benzyl-5.5-diethyl-2-((((CIS)-4-phenylcvclohexyl)oxy)methyl)pyrrolidin-3- yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42-2)
  • Step 3 N-((C/A)-l-benzyl-5.5-diethyl-2-((((CZS , )-4-phenylcvclohexyl)oxy)methyl)pyrrolidin-3- vDmethanesulfonamide (42-3)
  • Step 4 N-((CIS)-5.5-diethyl-2-((((CIS)-4-phenylcvclohexyl)oxy)methyl)pyrrolidin-3- vDmethanesulfonamide (42-4)
  • Step 5 methyl (CIS)-2.2-diethyl-4-(methylsulfonamido)-5-((((CIS)-4- phenylcvclohexyl)oxy)methyl)pyrrolidine-l -carboxylate (22)
  • Step 1 N-((2R.3S)-l-benzyl-5-ethyl-2-((((CIS)-4-phenylcvclohexyl)oxy)methyl)pynOlidin-3-yl)- N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (racemic) (43-1)
  • Step 2 N-((2R.3S.5R)-l-benzyl-5-ethyl-2-((((CIS)-4-phenylcvclohexyl)oxy)methyl)pyrrolidin-3- yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (racemic) (43-2)
  • Step 3 N-((2R.3S.5R)-5-ethyl-2-((((CIS)-4-phenylcvclohexyl)oxy)methyl)pyrrolidin-3- vDmethanesulfonamide (racemic) (43-3)
  • Step 4 methyl (2R.3S.5R)-5-ethyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcvclohexyl)- oxy)methyl)pyrrolidine-l-carboxylate (racemic) (43)
  • the following compound was prepared according to the general procedure provided in Examples 1-21, and procedures herein, by substituting the appropriate alkyl carbonochloridate and sulfamoyl chloride.
  • the starting materials are either prepared as described in the intermediates section, commercially available, or may be prepared from commercially available reagents using conventional reactions well known in the art.
  • Step 1 tert-butyl ((CIS)-3-(N-(4-methoxybenzyl)methylsulfonamido)-5-oxo-l-(((CIS)-4- phenylcvclohexyl)oxy)-7-(trimethylsilyl)hept-6-vn-2-yl)carbamate (47-11
  • Step 5 methyl (CIS)-5-ethynyl-3-(methylsulfonamido)-2-(((CIS)-4-4) (237.0 mg, 0.629 mmol) in DCM (4196 pi) was added METHYL CHLOROFORMATE (63.4 m ⁇ , 0.818 mmol) and TRIETHYLAMINE (175 m ⁇ , 1.259 mmol). The mixture stirred for 1 hour before concentrating. The residue was purified by column chromatography on C18 (5-95% MeCN/water with 0.05% TFA modifier) to afford the title compound. MS: 435.3 (M+l). 1H NMR (500 MHz,
  • Step 1 methyl (CIS)-5-formyl-3-(methylsulfonamido)-2-((((CIS)-4-phenylcvclohexyl)oxy)- methyl)pyrrolidine-l -carboxylate (50-1)
  • Step 2 methyl (CIS)-5-(hvdroxymethyl)-3-(methylsulfonamido)-2-((((CIS)-4- phenylcvclohexyl)oxy)methyl)pyrrolidine-l -carboxylate (50)
  • Step 1 dimethyl (2R.3S.5S)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-
  • Step 2 dimethyl (2R.3S.5S)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-
  • TRIFLUOROMETHANESULFONATE (89 mg, 0.348 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The resulting mixture was filtered through a pad of celite and concentrated. The residue was purified by column chromatography on silica (2% to 75% EtO Ac/hexanes) to afford the title compound. MS: 474.3 (M+l).
  • Step 3 methyl (2R.3S.5S)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-
  • Step 5 methyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-2-((((CIS)-4-
  • Step 1 dimethyl (2R.3S.5S)-3-((N.N-dimethylsulfamoyl)(4-methoxybenzyl)amino)-5-((((4- (trifluoromethyl)phenyl)sulfonyl)oxy)methyl)pynOlidine-1.2-dicarboxylate (52-1)
  • Step 2 dimethyl (2R.3S.5S)-5-(cvanomethyl)-3-((N.N-dimethylsulfamoyl)(4- methoxybenzyl)amino)pyrrolidine-1.2-dicarboxylate (52-2) To a mixture of dimethyl (2R,3S,5S)-3-((N,N-dimethylsulfamoyl)(4-methoxybenzyl)- amino)-5-((((4-(trifluoromethyl)phenyl)sulfonyl)oxy)methyl)pyrrolidine-l,2-dicarboxylate (52-1) (160 mg, 0.240 mmol) in DMSO (479 pi) at ambient temperature was added POTASSIUM CYANIDE (23.41 mg, 0.359 mmol).
  • Step 3 methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-
  • Step 5 methyl (2R,3S,5S)-5-(cyanomethyl)-3-((N,N-dimethylsulfamoyl)(4-
  • TRIMETHYLSILYL TRIFLUOROMETHANESULFONATE (16.29 m ⁇ , 0.090 mmol) was added dropwise. The mixture was warmed to 0 °C and stirred for 10 min before quenching with a saturated solution of NaHC03 (10 mL), extract with DCM (3x @ 10 mL), dry over Na2S04, and concentrate. The residue was purified by column chromatography on silica (0% to 50%
  • Step 1 methyl (2R.3S.5R)-2-((((ls.4S)-4-(3-fluorophenyl)cvclohexyl)oxy)methyl)-3- ((fluorosulfonyl)amino)-5-methylpyrrolidine-l -carboxylate (53-1) Methyl (2R,3S,5R)-3-amino-2-((((ls,4S)-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)-5- methylpyrrolidine-l-carboxylate (W) (176 mg, 0.381 mmol) in acetonitrile (5 ml) at 0 °C was added triethylamine (0.175 ml, 1.256 mmol) followed by l-(fluorosulfonyl)-2,3-dimethyl-lH- imidazol-3-ium methanesulfonate (231 mg, 0.842 m

Abstract

La présente invention concerne des composés 5-alkyl pyrrolidine qui sont des antagonistes des récepteurs de l'orexine. La présente invention concerne également des utilisations des composés décrits ici dans la prévention ou le traitement potentiel de troubles et de maladies neurologiques et psychiatriques dans lesquels les récepteurs de l'orexine sont impliqués. La présente invention concerne également des compositions comprenant ces composés. La présente invention concerne également des utilisations de ces compositions dans la prévention ou le traitement potentiel de telles maladies dans lesquelles sont impliqués des récepteurs de l'orexine.
PCT/US2020/017579 2019-02-13 2020-02-11 Agonistes du récepteur de l'orexine 5-alkyl-pyrrolidine WO2020167706A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US11028048B2 (en) 2019-01-31 2021-06-08 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
EP3816154A4 (fr) * 2018-06-29 2022-03-30 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son application
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US11760747B2 (en) 2020-12-21 2023-09-19 Alkermes, Inc. Substituted piperidino compounds and related methods of treatment

Citations (141)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3914250A (en) 1974-08-01 1975-10-21 American Home Prod 1,4-Diazepino{8 6,5,4-jk{9 carbazoles
US4973587A (en) 1990-03-08 1990-11-27 Sterling Drug Inc. 3-arylcarbonyl-1-aminoalkyl-1H-indole-containing antiglaucoma method
US5013837A (en) 1990-03-08 1991-05-07 Sterling Drug Inc. 3-Arylcarbonyl-1H-indole-containing compounds
US5081122A (en) 1990-03-05 1992-01-14 Sterling Drug Inc. Antiglaucoma compositions containing 4-arylcarbonyl-1-(4-morpholinyl)-lower-alkyl)-1H-indoles and method of use thereof
US5112820A (en) 1990-03-05 1992-05-12 Sterling Drug Inc. Anti-glaucoma compositions containing 2- and 3-aminomethyl-6-arylcarbonyl- or 6-phenylthio-2,3-dihydropyrrolo-(1,2,3-de)-1,4-benzoxazines and method of use thereof
US5162339A (en) 1988-11-23 1992-11-10 Pfizer Inc. Quinuclidine therapeutic agents
US5232929A (en) 1990-11-28 1993-08-03 Pfizer Inc. 3-aminopiperidine derivatives and related nitrogen containing heterocycles and pharmaceutical compositions and use
US5242930A (en) 1991-02-11 1993-09-07 Merck Sharp & Dohme Ltd. Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy
US5292736A (en) 1993-02-26 1994-03-08 Sterling Winthrop Inc. Morpholinoalkylindenes as antiglaucoma agents
US5373003A (en) 1991-03-01 1994-12-13 Pfizer Inc. 1-azabicyclo[3.2.2]nonan-3-amine derivatives
US5387595A (en) 1992-08-26 1995-02-07 Merck & Co., Inc. Alicyclic compounds as tachykinin receptor antagonists
US5459270A (en) 1991-08-20 1995-10-17 Merck Sharp & Dohme Limited Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them
US5494926A (en) 1992-05-27 1996-02-27 Merck Sharp & Dohme Ltd. 2/3-(heterocyclic alkyl amino)-1-(subst.-phenyl-methoxy)-ethanes/propanes as tachykinin-receptor antagonists
US5496833A (en) 1993-04-13 1996-03-05 Merck Sharp & Dohme Limited Piperidine tachykinin receptor antagonists
WO1996014307A1 (fr) 1994-11-07 1996-05-17 Pfizer Inc. Certains derives de benzylamine a substitutions; une nouvelle classe de ligands specifiques du neuropeptide y1
US5532237A (en) 1995-02-15 1996-07-02 Merck Frosst Canada, Inc. Indole derivatives with affinity for the cannabinoid receptor
US5536716A (en) 1992-12-11 1996-07-16 Merck & Co., Inc. Spiro piperidines and homologs which promote release of growth hormone
WO1996033159A1 (fr) 1995-04-21 1996-10-24 Abbott Laboratories Derives de cyclobutane utilises comme inhibiteurs de la synthase squalene et de la proteine farnesyltransferase
US5624941A (en) 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present
WO1997019682A1 (fr) 1995-12-01 1997-06-05 Synaptic Pharmaceutical Corporation Derives aryle sulfonamide et sulfamide, et leurs utilisations
US5637699A (en) 1992-06-29 1997-06-10 Merck & Co., Inc. Process for preparing morpholine tachykinin receptor antagonists
WO1997020822A1 (fr) 1995-12-01 1997-06-12 Novartis Ag Quinazolin-2,4-diazirines en tant qu'antagoniste du recepteur du neuropeptide y
WO1997020823A2 (fr) 1995-12-01 1997-06-12 Novartis Ag Antagonistes de recepteurs
WO1997020821A1 (fr) 1995-12-01 1997-06-12 Novartis Ag Derives heteroaryles
WO1997020820A1 (fr) 1995-12-01 1997-06-12 Novartis Ag Composes heteroaryles
WO1997028149A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Procede pour augmenter les niveaux de cholesterol hdl
WO1997029079A1 (fr) 1996-02-06 1997-08-14 Japan Tobacco Inc. Composes chimiques et utilisation pharmaceutique
WO1997036579A1 (fr) 1996-03-30 1997-10-09 Glaxo Group Limited Utilisation d'agonistes du recepteur alpha active par un proliferateur de peroxysome pour traiter l'obesite
US5739106A (en) 1995-06-07 1998-04-14 Rink; Timothy J. Appetite regulating compositions
WO1998024768A1 (fr) 1996-12-03 1998-06-11 Banyu Pharmaceutical Co., Ltd. Nouveaux derives d'uree
WO1998025908A1 (fr) 1996-12-13 1998-06-18 Banyu Pharmaceutical Co., Ltd. Nouveaux derives d'aminopyrazole
WO1998025907A1 (fr) 1996-12-12 1998-06-18 Banyu Pharmaceutical Co., Ltd. Derives de pyrazole
WO1998027063A1 (fr) 1996-12-16 1998-06-25 Banyu Pharmaceutical Co., Ltd. Derives d'aminopyrazole
WO1998031227A1 (fr) 1997-01-21 1998-07-23 Smithkline Beecham Corporation Nouveaux modulateurs de recepteurs de cannabinoides
WO1998033765A1 (fr) 1997-02-04 1998-08-06 E.I. Du Pont De Nemours And Company Carboxamides fongicides
WO1998037061A1 (fr) 1997-02-21 1998-08-27 Bayer Aktiengesellschaft Arylsulfonamides et leurs analogues, et procedes d'utilisation desdites substances pour traiter les maladies neurodegeneratives
WO1998040356A1 (fr) 1997-03-12 1998-09-17 Banyu Pharmaceutical Co., Ltd. Medicaments contenant des derives d'aminopyridine comme ingredient actif
WO1998041519A1 (fr) 1997-03-18 1998-09-24 Smithkline Beecham Corporation Nouveaux agonistes de recepteurs de cannabinoides
WO1998043636A1 (fr) 1997-03-28 1998-10-08 Sanofi-Synthelabo Composition pharmaceutique pour administration orale d'un derive du n-piperidino-3-pyrazolecarboxamide, de ses sels et de leurs s olvates
WO1998043635A1 (fr) 1997-03-28 1998-10-08 Sanofi-Synthelabo Composition pharmaceutique pour l'administration orale d'un derive du n-piperidino- 3-pyrazolecarboxamide, de ses sels et de leurs solvates
WO1998047505A1 (fr) 1997-04-23 1998-10-29 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur de neuropeptide y
WO1999002499A1 (fr) 1997-07-11 1999-01-21 Japan Tobacco Inc. Composes quinoline et utilisations de ceux-ci en medecine
WO1999015516A1 (fr) 1997-09-25 1999-04-01 Banyu Pharmaceutical Co., Ltd. Nouveaux antagonistes des recepteurs de neuropeptides y
WO1999027965A1 (fr) 1997-11-28 1999-06-10 Banyu Pharmaceutical Co., Ltd. Agents anti-hyperlipemiques
WO1999051600A1 (fr) 1998-04-02 1999-10-14 Neurogen Corporation DERIVES AMINOALKYLE SUBSTITUES DE 9H-PYRIDINO [2,3-b]INDOLE ET 9H-PYRIMIDINO [4,5-b]INDOLE
US6001836A (en) 1997-05-28 1999-12-14 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists: cyanoguanidine derivatives
US6028084A (en) 1995-11-23 2000-02-22 Sanofi-Synthelabo Pyrazole derivatives, method for preparing same, and pharmaceutical compositions containing said derivatives
WO2000010968A2 (fr) 1998-08-19 2000-03-02 Bayer Aktiengesellschaft Nouveaux esters d'aminoacides d'arylsulfonamides et leurs analogues
WO2000010967A1 (fr) 1998-08-19 2000-03-02 Bayer Aktiengesellschaft Nouveaux arylsulfonamides et leurs analogues
US6140354A (en) 1998-04-29 2000-10-31 Ortho-Mcneil Pharmaceutical, Inc. N-substituted aminotetralins as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders
WO2000064880A1 (fr) 1999-04-22 2000-11-02 Synaptic Pharmaceutical Corporation Antagonistes selectifs npy (y5)
WO2000068197A1 (fr) 1999-05-05 2000-11-16 Ortho-Mcneil Pharmaceutical, Inc. LIGANDS DE RECEPTEURS DU NEUROPEPTIDE Y DERIVES DE 3a,4,5,9b-TETRAHYDRO-1H-BENZ[e]INDOL-2-YL AMINE, UTILISES POUR LE TRAITEMENT DE L'OBESITE ET D'AUTRES ETATS PATHOLOGIQUES
WO2000069849A1 (fr) 1999-05-12 2000-11-23 Ortho-Mcneil Pharmaceutical, Inc. Carboxamides de pyrazole utiles pour le traitement de l'obesite et d'autres troubles
WO2001002379A1 (fr) 1999-06-30 2001-01-11 Synaptic Pharmaceutical Corporation Antagonistes selectifs du npy (y5)
WO2001007409A1 (fr) 1999-07-23 2001-02-01 Astrazeneca Uk Limited Derives de carbazole et leur utilisation en tant que ligands du recepteur de neuropeptide y5
WO2001009120A1 (fr) 1999-07-28 2001-02-08 Ortho-Mcneil Pharmaceutical, Inc. Derives d'amines et d'amides utilises en tant que ligands pour le recepteur y5 du neuropeptide y, utile dans le traitement de l'obesite et d'autres troubles
US6191160B1 (en) 1998-11-10 2001-02-20 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
WO2001014376A1 (fr) 1999-08-20 2001-03-01 Banyu Pharmaceutical Co., Ltd. Nouveaux composes spiro
WO2001021169A1 (fr) 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagonistes de l'hormone de concentration de la melanine
WO2001021577A2 (fr) 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2001023389A2 (fr) 1999-09-30 2001-04-05 Neurogen Corporation Hétérocycles à substitution alkylène-diamine
WO2001023388A2 (fr) 1999-09-30 2001-04-05 Neurogen Corporation Pyrazolo[1,5,-a]-1,5-pyrimidines et pyrazolo[1,5-a]-1,3,5-triazines amino substituees
WO2001023387A2 (fr) 1999-09-30 2001-04-05 Neurogen Corporation PYRAZOLO[1,5,-a]-1,5-PYRIMIDINES A SUBSTITUTION ALKYLENE-DIAMINE ET PYRAZOLO[1,5-a]-1,3,5-TRIAZINES
WO2001044201A1 (fr) 1999-12-16 2001-06-21 Schering Corporation Antagonistes du recepteur y5 au neuropeptide y a imidazoles substituees
WO2001056592A1 (fr) 2000-02-01 2001-08-09 Novo Nordisk A/S Utilisation de composes pour la regulation de l'absorption de nourriture
WO2001058869A2 (fr) 2000-02-11 2001-08-16 Bristol-Myers Squibb Company Modulateurs de recepteurs aux cannabinoides, leurs procedes de preparation et utilisations de modulateurs de recepteurs aux cannabinoides pour le traitement de maladies respiratoires et non respiratoires
WO2001062738A1 (fr) 2000-02-22 2001-08-30 Banyu Pharmaceutical Co., Ltd. Composes a base d'imidazoline
WO2001062737A2 (fr) 2000-02-24 2001-08-30 Ortho-Mcneil Pharmaceutical, Inc. Derives d'amino pyrazole utilises dans le traitement de l'obesite et d'autres troubles
WO2001064632A1 (fr) 2000-03-03 2001-09-07 Aventis Pharma S.A. Derives d'azetidine, leur preparation et les compositions pharmaceutiques les contenant
WO2001064633A1 (fr) 2000-03-03 2001-09-07 Aventis Pharma S.A. Compositions pharmaceutiques contenant des derives de 3-amino-azetidine, les nouveaux derives et leur preparation
WO2001064634A1 (fr) 2000-03-03 2001-09-07 Aventis Pharma S.A. Compositions pharmaceutiques contenant des derives d'azetidine, les nouveaux derives d'azetidine et leur preparation
WO2001066548A1 (fr) 2000-03-06 2001-09-13 F. Hoffmann-La Roche Ag Nouveaux derives aza-indolyle
WO2001077094A1 (fr) 2000-04-07 2001-10-18 Aventis Pharma Deutschland Gmbh Percyquinnine, procede pour sa production, et son utilisation comme medicament
WO2001082925A1 (fr) 2000-04-28 2001-11-08 Takeda Chemical Industries, Ltd. Antagonistes de l'hormone concentrant la melanine
WO2001085730A1 (fr) 2000-05-09 2001-11-15 Astrazeneca Ab Derives de pyrido' 1,2-alpha pyrazine et de piperidine servant de ligands au recepteur de neuropeptide y y5
WO2001085098A2 (fr) 2000-05-10 2001-11-15 Bristol-Myers Squibb Company Derives de dihydropyridine a squarate antagonistes de npy
WO2001085173A1 (fr) 2000-05-10 2001-11-15 Bristol-Myers Squibb Company Derives d'alkylamine d'antagonistes de dihydropyridine npy
WO2001085714A1 (fr) 2000-05-05 2001-11-15 Astrazeneca Ab Derives de dibenzothiophene amino substitutes destines au traitement de troubles induits par le recepteur du neuropeptide y5
WO2001085690A1 (fr) 2000-05-10 2001-11-15 Bristol-Myers Squibb Company Derives 4-alkyle et 4-cycloalkyle d'antagonistes de npy de dihydropyridine
WO2001087834A1 (fr) 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2001087335A2 (fr) 2000-05-17 2001-11-22 Eli Lilly And Company Procede d'inhibition selective de la ghreline
WO2001090090A1 (fr) 2000-05-22 2001-11-29 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy-steroide-deshydrogenase de type 1
WO2001089528A1 (fr) 2000-05-19 2001-11-29 Bristol-Myers Squibb Company Derives thio-uree de dihydropyridines possedant une activite d'antagonistes de npy
US6329395B1 (en) 1998-06-08 2001-12-11 Schering Corporation Neuropeptide Y5 receptor antagonists
US6337332B1 (en) 1998-09-17 2002-01-08 Pfizer Inc. Neuropeptide Y receptor antagonists
WO2002004433A2 (fr) 2000-07-06 2002-01-17 Neurogen Corporation Ligands de recepteur d'hormone a concentration de melanine
US6340683B1 (en) 1999-04-22 2002-01-22 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (triazines)
WO2002006245A1 (fr) 2000-07-05 2002-01-24 Synaptic Pharmarceutical Corporation Antagonistes selectifs des recepteurs (mch1) d'hormone-1 de concentration de la melanine et utilisation de ceux-ci
WO2002008250A2 (fr) 2000-07-24 2002-01-31 Ardana Bioscience Limited Antagonistes de la ghreline
WO2002010169A1 (fr) 2000-07-31 2002-02-07 F. Hoffmann-La Roche Ag Derives de la piperazine
US20020022637A1 (en) 2000-05-11 2002-02-21 Li James J. Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
US6358951B1 (en) 1998-08-21 2002-03-19 Pfizer Inc. Growth hormone secretagogues
WO2002022592A2 (fr) 2000-09-14 2002-03-21 Schering Corporation Antagonistes du recepteur y.y5 de neuropeptide d'urease substitue
US20020049196A1 (en) 1995-12-28 2002-04-25 Carpino Philip A. Growth-hormone secretagogues
WO2002032888A1 (fr) 2000-10-13 2002-04-25 Eli Lilly And Company Dipeptides a substitution en tant que secretagogues d'hormone de croissance
WO2002036596A2 (fr) 2000-11-03 2002-05-10 Wyeth Cycloalkyl[b][1,4]diazepino[6,7,1-hi]indoles et derives
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
WO2002040456A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazine utilises comme agonistes ou antagonistes du recepteur de la serotonine 5ht-2
WO2002044152A1 (fr) 2000-10-16 2002-06-06 F. Hoffmann-La Roche Ag Derives d'indoline et leur utilisation en tant que ligands de recepteur 5-ht2
WO2002048124A2 (fr) 2000-12-15 2002-06-20 F. Hoffmann-La Roche Ag Derives de piperazine
WO2002048152A2 (fr) 2000-12-12 2002-06-20 Neurogen Corporation Spiro[isobenzofuran-1,4'-piperidine]-3-ones et 3h-spiroisobenzofuran-1,4'-piperidines
WO2002049648A1 (fr) 2000-12-21 2002-06-27 Schering Corporation Antagonistes du recepteur de neuropeptide y y5 d'uree heteroaryle
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2002051809A1 (fr) 2000-12-22 2002-07-04 Schering Corporation Antagonistes piperidiniques de mch et leur utilisation dans le traitement de l'obesite
WO2002051844A1 (fr) 2000-12-27 2002-07-04 F. Hoffmann-La Roche Ag Derives d'indole et leur utilisation en tant que ligands de recepteurs 5-ht2b et 5-ht2c
WO2002062764A1 (fr) 2001-02-02 2002-08-15 Takeda Chemical Industries, Ltd. Composes heterocycliques condenses
WO2002076929A1 (fr) 2001-03-21 2002-10-03 Pharmacopeia, Inc. Composes d'aryle et de biaryle ayant une activite modulatrice de mch
WO2002076949A1 (fr) 2001-03-22 2002-10-03 Solvay Pharmaceuticals B.V. Derives de 4,5-dihydro-1h-pyrazole ayant une activite d'antagoniste de cb¿1?
WO2002076947A1 (fr) 2001-03-21 2002-10-03 Schering Corporation Antagonistes de l'hormone concentrant la melanine (mch) et leur utilisation dans le traitement de l'obesite
US6462053B1 (en) 1999-08-20 2002-10-08 Banyu Pharmaceutical Co., Ltd. Spiro compounds
WO2002083134A1 (fr) 2001-04-12 2002-10-24 Pharmacopeia, Inc. Aryl et biaryl piperidines utilisees en tant qu'antagonistes de la mch
WO2002083128A1 (fr) 2001-04-12 2002-10-24 Bristol-Myers Squibb Company Inhibiteurs a base de 2,1-oxazoline et 1,2-pyrazoline de la dipeptidyl peptidase iv et methode associee
EP1258476A1 (fr) 2001-05-15 2002-11-20 Les Laboratoires Servier Dérivés d'alpha-amino-acides, leur procédé de préparation ainsi que leur utilisation en tant qu'inhibiteurs de dipeptidyl-peptidase IV (DPP IV)
WO2002094799A2 (fr) 2001-05-22 2002-11-28 Neurogen Corporation Ligands recepteurs de l'hormone de concentration de la melanine: analogues de 1-benzyl-4-aryl piperazine substituee
WO2002094825A1 (fr) 2001-05-22 2002-11-28 Banyu Pharmaceutical Co., Ltd. Nouveau derive de spiropiperidine
WO2003000180A2 (fr) 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyle peptidase pour le traitement du diabete
WO2003000250A1 (fr) 2001-06-25 2003-01-03 Ferring Bv Agents antidiabetiques a base de 3-fluoro-pyrrolidines
WO2003000181A2 (fr) 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyl peptidase utilises dans le traitement du diabete
WO2003002553A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003002593A2 (fr) 2001-06-27 2003-01-09 Probiodrug Ag Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv
WO2003002530A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Pyrrolidines servant d'inhibiteurs de dipeptidyl peptidase
WO2003002531A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003004498A1 (fr) 2001-07-06 2003-01-16 Merck & Co., Inc. Pyrazines beta-amino tetrahydroimidazo (1, 2-a) et pyrazines tetrahydrotrioazolo (4, 3-a) utilisees en tant qu'inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
WO2003004496A1 (fr) 2001-07-03 2003-01-16 Novo Nordisk A/S Derives de purine inhibiteurs de dpp-iv pour le traitement du diabete
WO2003004027A1 (fr) 2001-07-05 2003-01-16 Synaptic Pharmaceutical Corporation Piperidines aniliniques substituees, utilisees comme antagonistes selectifs de la mch
WO2003007887A2 (fr) 2001-07-20 2003-01-30 Merck & Co., Inc. Imidazoles substitues servant de modulateurs de recepteurs de cannabinoides
WO2003010191A1 (fr) 2001-07-27 2003-02-06 Empresa Brasileira De Pesquisa Agropecuária - Embrapa Nouveaux peptides cationiques appartenant a la famille des dermaseptines isoles a partir de la secretion cutanee des phyllomedusa hypochondrialis
WO2003014083A1 (fr) 2001-08-07 2003-02-20 Banyu Pharmaceutical Co., Ltd. Composes spiro
WO2003092889A1 (fr) 2002-05-01 2003-11-13 Banyu Pharmaceutical Co., Ltd. Procede de preparation de derives de 2-aminopyrazine
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
WO2004031175A2 (fr) 2002-09-30 2004-04-15 Banyu Pharmaceutical Co., Ltd. Derives de -2-oxodihydropyridine a substitution n
US6730690B2 (en) 2002-06-10 2004-05-04 Merck & Co., Inc. 11-β-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia
WO2004048317A1 (fr) 2002-11-22 2004-06-10 Merck & Co., Inc. Amides substitues actifs au niveau du recepteur de cannabinoide-1
US20040133011A1 (en) 2002-12-20 2004-07-08 Waddell Sherman T. Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
WO2005000809A1 (fr) 2003-06-11 2005-01-06 Merck & Co., Inc. Derives 3-alkyle et 3-alcenyle azetidine substitues
US9527807B2 (en) 2011-04-05 2016-12-27 Takeda Pharmaceutical Company Limited Sulfonamide derivative and use thereof
WO2017135306A1 (fr) 2016-02-04 2017-08-10 Takeda Pharmaceutical Company Limited Composé de pipéridine substituée et son utilisation
WO2018164191A1 (fr) 2017-03-08 2018-09-13 武田薬品工業株式会社 Composé de pyrrolidine substituée et son utilisation
WO2018164192A1 (fr) 2017-03-08 2018-09-13 武田薬品工業株式会社 Composé de pyrrolidine substituée et son utilisation
WO2019027003A1 (fr) 2017-08-03 2019-02-07 武田薬品工業株式会社 Composé hétérocyclique et son application
WO2019027058A1 (fr) 2017-08-03 2019-02-07 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015827A1 (fr) 2004-08-09 2006-02-16 Glaxo Group Limited Composés potentialisateurs de récepteur de glutamate et utilisations de ceux-ci en médecine
ATE540944T1 (de) 2007-05-23 2012-01-15 Merck Sharp & Dohme Pyridylpiperidinorexin-rezeptorantagonisten
AU2008260647A1 (en) 2007-05-23 2008-12-11 Merck Sharp & Dohme Corp. Cyclopropyl pyrrolidine orexin receptor antagonists
WO2009133522A1 (fr) 2008-04-30 2009-11-05 Actelion Pharmaceuticals Ltd Composés de pipéridine et de pyrrolidine
CA2739919A1 (fr) 2008-10-21 2010-04-29 Merck Sharp & Dohme Corp. Antagonistes de recepteur de l'orexine de type pyrrolidine 2,4-disubstituee
WO2012058129A1 (fr) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. Procédé de préparation d'un antagoniste du récepteur de l'orexine
WO2014006402A1 (fr) 2012-07-03 2014-01-09 Heptares Therapeutics Limited Antagonistes du récepteur de l'orexine
WO2016095204A1 (fr) 2014-12-19 2016-06-23 Merck Sharp & Dohme Corp. Composés pyrrolidine en tant qu'antagonistes du récepteur de l'hypocrétine
WO2019089991A1 (fr) 2017-11-01 2019-05-09 The Regents Of The University Of California Nouveaux agents ciblant des protéines inhibitrices de l'apoptose
EP3816153B1 (fr) 2018-06-29 2023-10-18 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
EP3816154A4 (fr) 2018-06-29 2022-03-30 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son application

Patent Citations (158)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3914250A (en) 1974-08-01 1975-10-21 American Home Prod 1,4-Diazepino{8 6,5,4-jk{9 carbazoles
US5162339A (en) 1988-11-23 1992-11-10 Pfizer Inc. Quinuclidine therapeutic agents
US5081122A (en) 1990-03-05 1992-01-14 Sterling Drug Inc. Antiglaucoma compositions containing 4-arylcarbonyl-1-(4-morpholinyl)-lower-alkyl)-1H-indoles and method of use thereof
US5112820A (en) 1990-03-05 1992-05-12 Sterling Drug Inc. Anti-glaucoma compositions containing 2- and 3-aminomethyl-6-arylcarbonyl- or 6-phenylthio-2,3-dihydropyrrolo-(1,2,3-de)-1,4-benzoxazines and method of use thereof
US4973587A (en) 1990-03-08 1990-11-27 Sterling Drug Inc. 3-arylcarbonyl-1-aminoalkyl-1H-indole-containing antiglaucoma method
US5013837A (en) 1990-03-08 1991-05-07 Sterling Drug Inc. 3-Arylcarbonyl-1H-indole-containing compounds
US5232929A (en) 1990-11-28 1993-08-03 Pfizer Inc. 3-aminopiperidine derivatives and related nitrogen containing heterocycles and pharmaceutical compositions and use
US5242930A (en) 1991-02-11 1993-09-07 Merck Sharp & Dohme Ltd. Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy
US5373003A (en) 1991-03-01 1994-12-13 Pfizer Inc. 1-azabicyclo[3.2.2]nonan-3-amine derivatives
US5459270A (en) 1991-08-20 1995-10-17 Merck Sharp & Dohme Limited Azacyclic compounds, processes for their preparation and pharmaceutical compositions containing them
US5494926A (en) 1992-05-27 1996-02-27 Merck Sharp & Dohme Ltd. 2/3-(heterocyclic alkyl amino)-1-(subst.-phenyl-methoxy)-ethanes/propanes as tachykinin-receptor antagonists
US5624941A (en) 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present
US5637699A (en) 1992-06-29 1997-06-10 Merck & Co., Inc. Process for preparing morpholine tachykinin receptor antagonists
US5387595A (en) 1992-08-26 1995-02-07 Merck & Co., Inc. Alicyclic compounds as tachykinin receptor antagonists
US5536716A (en) 1992-12-11 1996-07-16 Merck & Co., Inc. Spiro piperidines and homologs which promote release of growth hormone
US5292736A (en) 1993-02-26 1994-03-08 Sterling Winthrop Inc. Morpholinoalkylindenes as antiglaucoma agents
US5496833A (en) 1993-04-13 1996-03-05 Merck Sharp & Dohme Limited Piperidine tachykinin receptor antagonists
WO1996014307A1 (fr) 1994-11-07 1996-05-17 Pfizer Inc. Certains derives de benzylamine a substitutions; une nouvelle classe de ligands specifiques du neuropeptide y1
US5532237A (en) 1995-02-15 1996-07-02 Merck Frosst Canada, Inc. Indole derivatives with affinity for the cannabinoid receptor
WO1996033159A1 (fr) 1995-04-21 1996-10-24 Abbott Laboratories Derives de cyclobutane utilises comme inhibiteurs de la synthase squalene et de la proteine farnesyltransferase
US5739106A (en) 1995-06-07 1998-04-14 Rink; Timothy J. Appetite regulating compositions
US6028084A (en) 1995-11-23 2000-02-22 Sanofi-Synthelabo Pyrazole derivatives, method for preparing same, and pharmaceutical compositions containing said derivatives
WO1997020820A1 (fr) 1995-12-01 1997-06-12 Novartis Ag Composes heteroaryles
WO1997020821A1 (fr) 1995-12-01 1997-06-12 Novartis Ag Derives heteroaryles
WO1997020822A1 (fr) 1995-12-01 1997-06-12 Novartis Ag Quinazolin-2,4-diazirines en tant qu'antagoniste du recepteur du neuropeptide y
WO1997020823A2 (fr) 1995-12-01 1997-06-12 Novartis Ag Antagonistes de recepteurs
WO1997019682A1 (fr) 1995-12-01 1997-06-05 Synaptic Pharmaceutical Corporation Derives aryle sulfonamide et sulfamide, et leurs utilisations
US20020049196A1 (en) 1995-12-28 2002-04-25 Carpino Philip A. Growth-hormone secretagogues
WO1997028149A1 (fr) 1996-02-02 1997-08-07 Merck & Co., Inc. Procede pour augmenter les niveaux de cholesterol hdl
WO1997029079A1 (fr) 1996-02-06 1997-08-14 Japan Tobacco Inc. Composes chimiques et utilisation pharmaceutique
WO1997036579A1 (fr) 1996-03-30 1997-10-09 Glaxo Group Limited Utilisation d'agonistes du recepteur alpha active par un proliferateur de peroxysome pour traiter l'obesite
US6043246A (en) 1996-12-03 2000-03-28 Banyu Pharmaceutical Co., Ltd. Urea derivatives
WO1998024768A1 (fr) 1996-12-03 1998-06-11 Banyu Pharmaceutical Co., Ltd. Nouveaux derives d'uree
WO1998025907A1 (fr) 1996-12-12 1998-06-18 Banyu Pharmaceutical Co., Ltd. Derives de pyrazole
US6057335A (en) 1996-12-12 2000-05-02 Banyu Pharmaceutical Co., Ltd. Pyrazole derivatives
WO1998025908A1 (fr) 1996-12-13 1998-06-18 Banyu Pharmaceutical Co., Ltd. Nouveaux derives d'aminopyrazole
US6166038A (en) 1996-12-13 2000-12-26 Banyu Pharmaceutical Co., Ltd. Aminopyrazole derivatives
WO1998027063A1 (fr) 1996-12-16 1998-06-25 Banyu Pharmaceutical Co., Ltd. Derives d'aminopyrazole
US6180653B1 (en) 1996-12-16 2001-01-30 Banyu Pharmaceutical Co., Ltd. Aminopyrazole derivatives
WO1998031227A1 (fr) 1997-01-21 1998-07-23 Smithkline Beecham Corporation Nouveaux modulateurs de recepteurs de cannabinoides
WO1998033765A1 (fr) 1997-02-04 1998-08-06 E.I. Du Pont De Nemours And Company Carboxamides fongicides
WO1998037061A1 (fr) 1997-02-21 1998-08-27 Bayer Aktiengesellschaft Arylsulfonamides et leurs analogues, et procedes d'utilisation desdites substances pour traiter les maladies neurodegeneratives
WO1998040356A1 (fr) 1997-03-12 1998-09-17 Banyu Pharmaceutical Co., Ltd. Medicaments contenant des derives d'aminopyridine comme ingredient actif
WO1998041519A1 (fr) 1997-03-18 1998-09-24 Smithkline Beecham Corporation Nouveaux agonistes de recepteurs de cannabinoides
WO1998043635A1 (fr) 1997-03-28 1998-10-08 Sanofi-Synthelabo Composition pharmaceutique pour l'administration orale d'un derive du n-piperidino- 3-pyrazolecarboxamide, de ses sels et de leurs solvates
WO1998043636A1 (fr) 1997-03-28 1998-10-08 Sanofi-Synthelabo Composition pharmaceutique pour administration orale d'un derive du n-piperidino-3-pyrazolecarboxamide, de ses sels et de leurs s olvates
WO1998047505A1 (fr) 1997-04-23 1998-10-29 Banyu Pharmaceutical Co., Ltd. Antagoniste de recepteur de neuropeptide y
US6001836A (en) 1997-05-28 1999-12-14 Bristol-Myers Squibb Company Dihydropyridine NPY antagonists: cyanoguanidine derivatives
WO1999002499A1 (fr) 1997-07-11 1999-01-21 Japan Tobacco Inc. Composes quinoline et utilisations de ceux-ci en medecine
WO1999015516A1 (fr) 1997-09-25 1999-04-01 Banyu Pharmaceutical Co., Ltd. Nouveaux antagonistes des recepteurs de neuropeptides y
WO1999027965A1 (fr) 1997-11-28 1999-06-10 Banyu Pharmaceutical Co., Ltd. Agents anti-hyperlipemiques
WO1999051600A1 (fr) 1998-04-02 1999-10-14 Neurogen Corporation DERIVES AMINOALKYLE SUBSTITUES DE 9H-PYRIDINO [2,3-b]INDOLE ET 9H-PYRIMIDINO [4,5-b]INDOLE
US6140354A (en) 1998-04-29 2000-10-31 Ortho-Mcneil Pharmaceutical, Inc. N-substituted aminotetralins as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders
US6329395B1 (en) 1998-06-08 2001-12-11 Schering Corporation Neuropeptide Y5 receptor antagonists
WO2000010967A1 (fr) 1998-08-19 2000-03-02 Bayer Aktiengesellschaft Nouveaux arylsulfonamides et leurs analogues
WO2000010968A2 (fr) 1998-08-19 2000-03-02 Bayer Aktiengesellschaft Nouveaux esters d'aminoacides d'arylsulfonamides et leurs analogues
US6358951B1 (en) 1998-08-21 2002-03-19 Pfizer Inc. Growth hormone secretagogues
US6337332B1 (en) 1998-09-17 2002-01-08 Pfizer Inc. Neuropeptide Y receptor antagonists
US6191160B1 (en) 1998-11-10 2001-02-20 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6313298B1 (en) 1998-11-10 2001-11-06 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
WO2000064880A1 (fr) 1999-04-22 2000-11-02 Synaptic Pharmaceutical Corporation Antagonistes selectifs npy (y5)
US6340683B1 (en) 1999-04-22 2002-01-22 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (triazines)
WO2000068197A1 (fr) 1999-05-05 2000-11-16 Ortho-Mcneil Pharmaceutical, Inc. LIGANDS DE RECEPTEURS DU NEUROPEPTIDE Y DERIVES DE 3a,4,5,9b-TETRAHYDRO-1H-BENZ[e]INDOL-2-YL AMINE, UTILISES POUR LE TRAITEMENT DE L'OBESITE ET D'AUTRES ETATS PATHOLOGIQUES
WO2000069849A1 (fr) 1999-05-12 2000-11-23 Ortho-Mcneil Pharmaceutical, Inc. Carboxamides de pyrazole utiles pour le traitement de l'obesite et d'autres troubles
WO2001002379A1 (fr) 1999-06-30 2001-01-11 Synaptic Pharmaceutical Corporation Antagonistes selectifs du npy (y5)
WO2001007409A1 (fr) 1999-07-23 2001-02-01 Astrazeneca Uk Limited Derives de carbazole et leur utilisation en tant que ligands du recepteur de neuropeptide y5
WO2001009120A1 (fr) 1999-07-28 2001-02-08 Ortho-Mcneil Pharmaceutical, Inc. Derives d'amines et d'amides utilises en tant que ligands pour le recepteur y5 du neuropeptide y, utile dans le traitement de l'obesite et d'autres troubles
US6388077B1 (en) 1999-08-20 2002-05-14 Banyu Pharmaceutical Co., Ltd. Spiro compounds
US6335345B1 (en) 1999-08-20 2002-01-01 Banyu Pharmaceutical Co., Ltd. Spiro compounds
US6326375B1 (en) 1999-08-20 2001-12-04 Banyu Pharmaceutical Co., Ltd. Spiro compounds
US6462053B1 (en) 1999-08-20 2002-10-08 Banyu Pharmaceutical Co., Ltd. Spiro compounds
US6649624B2 (en) 1999-08-20 2003-11-18 Banyu Pharmaceutical Co., Ltd. Spiro compounds
US6723847B2 (en) 1999-08-20 2004-04-20 Banyu Pharmaceutical Co., Ltd. Spiro compounds
WO2001014376A1 (fr) 1999-08-20 2001-03-01 Banyu Pharmaceutical Co., Ltd. Nouveaux composes spiro
WO2001021577A2 (fr) 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2001021169A1 (fr) 1999-09-20 2001-03-29 Takeda Chemical Industries, Ltd. Antagonistes de l'hormone de concentration de la melanine
US6414002B1 (en) 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2001023387A2 (fr) 1999-09-30 2001-04-05 Neurogen Corporation PYRAZOLO[1,5,-a]-1,5-PYRIMIDINES A SUBSTITUTION ALKYLENE-DIAMINE ET PYRAZOLO[1,5-a]-1,3,5-TRIAZINES
WO2001023388A2 (fr) 1999-09-30 2001-04-05 Neurogen Corporation Pyrazolo[1,5,-a]-1,5-pyrimidines et pyrazolo[1,5-a]-1,3,5-triazines amino substituees
WO2001023389A2 (fr) 1999-09-30 2001-04-05 Neurogen Corporation Hétérocycles à substitution alkylène-diamine
WO2001044201A1 (fr) 1999-12-16 2001-06-21 Schering Corporation Antagonistes du recepteur y5 au neuropeptide y a imidazoles substituees
WO2001056592A1 (fr) 2000-02-01 2001-08-09 Novo Nordisk A/S Utilisation de composes pour la regulation de l'absorption de nourriture
WO2001058869A2 (fr) 2000-02-11 2001-08-16 Bristol-Myers Squibb Company Modulateurs de recepteurs aux cannabinoides, leurs procedes de preparation et utilisations de modulateurs de recepteurs aux cannabinoides pour le traitement de maladies respiratoires et non respiratoires
WO2001062738A1 (fr) 2000-02-22 2001-08-30 Banyu Pharmaceutical Co., Ltd. Composes a base d'imidazoline
WO2001062737A2 (fr) 2000-02-24 2001-08-30 Ortho-Mcneil Pharmaceutical, Inc. Derives d'amino pyrazole utilises dans le traitement de l'obesite et d'autres troubles
WO2001064634A1 (fr) 2000-03-03 2001-09-07 Aventis Pharma S.A. Compositions pharmaceutiques contenant des derives d'azetidine, les nouveaux derives d'azetidine et leur preparation
WO2001064633A1 (fr) 2000-03-03 2001-09-07 Aventis Pharma S.A. Compositions pharmaceutiques contenant des derives de 3-amino-azetidine, les nouveaux derives et leur preparation
WO2001064632A1 (fr) 2000-03-03 2001-09-07 Aventis Pharma S.A. Derives d'azetidine, leur preparation et les compositions pharmaceutiques les contenant
WO2001066548A1 (fr) 2000-03-06 2001-09-13 F. Hoffmann-La Roche Ag Nouveaux derives aza-indolyle
WO2001077094A1 (fr) 2000-04-07 2001-10-18 Aventis Pharma Deutschland Gmbh Percyquinnine, procede pour sa production, et son utilisation comme medicament
WO2001082925A1 (fr) 2000-04-28 2001-11-08 Takeda Chemical Industries, Ltd. Antagonistes de l'hormone concentrant la melanine
WO2001085714A1 (fr) 2000-05-05 2001-11-15 Astrazeneca Ab Derives de dibenzothiophene amino substitutes destines au traitement de troubles induits par le recepteur du neuropeptide y5
WO2001085730A1 (fr) 2000-05-09 2001-11-15 Astrazeneca Ab Derives de pyrido' 1,2-alpha pyrazine et de piperidine servant de ligands au recepteur de neuropeptide y y5
WO2001085690A1 (fr) 2000-05-10 2001-11-15 Bristol-Myers Squibb Company Derives 4-alkyle et 4-cycloalkyle d'antagonistes de npy de dihydropyridine
WO2001085173A1 (fr) 2000-05-10 2001-11-15 Bristol-Myers Squibb Company Derives d'alkylamine d'antagonistes de dihydropyridine npy
WO2001085098A2 (fr) 2000-05-10 2001-11-15 Bristol-Myers Squibb Company Derives de dihydropyridine a squarate antagonistes de npy
US20020022637A1 (en) 2000-05-11 2002-02-21 Li James J. Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
WO2001087834A1 (fr) 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
WO2001087335A2 (fr) 2000-05-17 2001-11-22 Eli Lilly And Company Procede d'inhibition selective de la ghreline
WO2001089528A1 (fr) 2000-05-19 2001-11-29 Bristol-Myers Squibb Company Derives thio-uree de dihydropyridines possedant une activite d'antagonistes de npy
WO2001090091A1 (fr) 2000-05-22 2001-11-29 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy-steroide-deshydrogenase de type 1
WO2001090090A1 (fr) 2000-05-22 2001-11-29 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy-steroide-deshydrogenase de type 1
WO2001090092A1 (fr) 2000-05-22 2001-11-29 Biovitrum Ab Inhibiteurs de 11-beta-hydroxy-steroide-deshydrogenase de type 1
WO2002006245A1 (fr) 2000-07-05 2002-01-24 Synaptic Pharmarceutical Corporation Antagonistes selectifs des recepteurs (mch1) d'hormone-1 de concentration de la melanine et utilisation de ceux-ci
WO2002004433A2 (fr) 2000-07-06 2002-01-17 Neurogen Corporation Ligands de recepteur d'hormone a concentration de melanine
WO2002008250A2 (fr) 2000-07-24 2002-01-31 Ardana Bioscience Limited Antagonistes de la ghreline
WO2002010169A1 (fr) 2000-07-31 2002-02-07 F. Hoffmann-La Roche Ag Derives de la piperazine
WO2002022592A2 (fr) 2000-09-14 2002-03-21 Schering Corporation Antagonistes du recepteur y.y5 de neuropeptide d'urease substitue
WO2002032888A1 (fr) 2000-10-13 2002-04-25 Eli Lilly And Company Dipeptides a substitution en tant que secretagogues d'hormone de croissance
WO2002044152A1 (fr) 2000-10-16 2002-06-06 F. Hoffmann-La Roche Ag Derives d'indoline et leur utilisation en tant que ligands de recepteur 5-ht2
WO2002036596A2 (fr) 2000-11-03 2002-05-10 Wyeth Cycloalkyl[b][1,4]diazepino[6,7,1-hi]indoles et derives
WO2002040456A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazine utilises comme agonistes ou antagonistes du recepteur de la serotonine 5ht-2
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
WO2002048152A2 (fr) 2000-12-12 2002-06-20 Neurogen Corporation Spiro[isobenzofuran-1,4'-piperidine]-3-ones et 3h-spiroisobenzofuran-1,4'-piperidines
WO2002048124A2 (fr) 2000-12-15 2002-06-20 F. Hoffmann-La Roche Ag Derives de piperazine
WO2002049648A1 (fr) 2000-12-21 2002-06-27 Schering Corporation Antagonistes du recepteur de neuropeptide y y5 d'uree heteroaryle
WO2002051809A1 (fr) 2000-12-22 2002-07-04 Schering Corporation Antagonistes piperidiniques de mch et leur utilisation dans le traitement de l'obesite
WO2002051844A1 (fr) 2000-12-27 2002-07-04 F. Hoffmann-La Roche Ag Derives d'indole et leur utilisation en tant que ligands de recepteurs 5-ht2b et 5-ht2c
WO2002062764A1 (fr) 2001-02-02 2002-08-15 Takeda Chemical Industries, Ltd. Composes heterocycliques condenses
WO2002076947A1 (fr) 2001-03-21 2002-10-03 Schering Corporation Antagonistes de l'hormone concentrant la melanine (mch) et leur utilisation dans le traitement de l'obesite
WO2002076929A1 (fr) 2001-03-21 2002-10-03 Pharmacopeia, Inc. Composes d'aryle et de biaryle ayant une activite modulatrice de mch
WO2002076949A1 (fr) 2001-03-22 2002-10-03 Solvay Pharmaceuticals B.V. Derives de 4,5-dihydro-1h-pyrazole ayant une activite d'antagoniste de cb¿1?
WO2002083134A1 (fr) 2001-04-12 2002-10-24 Pharmacopeia, Inc. Aryl et biaryl piperidines utilisees en tant qu'antagonistes de la mch
WO2002083128A1 (fr) 2001-04-12 2002-10-24 Bristol-Myers Squibb Company Inhibiteurs a base de 2,1-oxazoline et 1,2-pyrazoline de la dipeptidyl peptidase iv et methode associee
EP1258476A1 (fr) 2001-05-15 2002-11-20 Les Laboratoires Servier Dérivés d'alpha-amino-acides, leur procédé de préparation ainsi que leur utilisation en tant qu'inhibiteurs de dipeptidyl-peptidase IV (DPP IV)
WO2002094799A2 (fr) 2001-05-22 2002-11-28 Neurogen Corporation Ligands recepteurs de l'hormone de concentration de la melanine: analogues de 1-benzyl-4-aryl piperazine substituee
WO2002094825A1 (fr) 2001-05-22 2002-11-28 Banyu Pharmaceutical Co., Ltd. Nouveau derive de spiropiperidine
WO2003000180A2 (fr) 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyle peptidase pour le traitement du diabete
WO2003000181A2 (fr) 2001-06-20 2003-01-03 Merck & Co., Inc. Inhibiteurs de dipeptidyl peptidase utilises dans le traitement du diabete
WO2003000250A1 (fr) 2001-06-25 2003-01-03 Ferring Bv Agents antidiabetiques a base de 3-fluoro-pyrrolidines
WO2003002553A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003002593A2 (fr) 2001-06-27 2003-01-09 Probiodrug Ag Structures peptidiques utiles pour la modulation competitive de la catalyse de dipeptidyle peptidase iv
WO2003002530A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Pyrrolidines servant d'inhibiteurs de dipeptidyl peptidase
WO2003002531A2 (fr) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines inhibitrices de la dipeptidyl peptidase
WO2003004496A1 (fr) 2001-07-03 2003-01-16 Novo Nordisk A/S Derives de purine inhibiteurs de dpp-iv pour le traitement du diabete
WO2003004027A1 (fr) 2001-07-05 2003-01-16 Synaptic Pharmaceutical Corporation Piperidines aniliniques substituees, utilisees comme antagonistes selectifs de la mch
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2003004498A1 (fr) 2001-07-06 2003-01-16 Merck & Co., Inc. Pyrazines beta-amino tetrahydroimidazo (1, 2-a) et pyrazines tetrahydrotrioazolo (4, 3-a) utilisees en tant qu'inhibiteurs de la dipeptidyl peptidase dans le traitement ou la prevention du diabete
WO2003007887A2 (fr) 2001-07-20 2003-01-30 Merck & Co., Inc. Imidazoles substitues servant de modulateurs de recepteurs de cannabinoides
WO2003010191A1 (fr) 2001-07-27 2003-02-06 Empresa Brasileira De Pesquisa Agropecuária - Embrapa Nouveaux peptides cationiques appartenant a la famille des dermaseptines isoles a partir de la secretion cutanee des phyllomedusa hypochondrialis
WO2003014083A1 (fr) 2001-08-07 2003-02-20 Banyu Pharmaceutical Co., Ltd. Composes spiro
WO2003092889A1 (fr) 2002-05-01 2003-11-13 Banyu Pharmaceutical Co., Ltd. Procede de preparation de derives de 2-aminopyrazine
US6730690B2 (en) 2002-06-10 2004-05-04 Merck & Co., Inc. 11-β-hydroxysteroid dehydrogenase 1 inhibitors useful for the treatment of diabetes, obesity and dyslipidemia
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
WO2004031175A2 (fr) 2002-09-30 2004-04-15 Banyu Pharmaceutical Co., Ltd. Derives de -2-oxodihydropyridine a substitution n
WO2004048317A1 (fr) 2002-11-22 2004-06-10 Merck & Co., Inc. Amides substitues actifs au niveau du recepteur de cannabinoide-1
US20040133011A1 (en) 2002-12-20 2004-07-08 Waddell Sherman T. Triazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1
WO2005000809A1 (fr) 2003-06-11 2005-01-06 Merck & Co., Inc. Derives 3-alkyle et 3-alcenyle azetidine substitues
US9527807B2 (en) 2011-04-05 2016-12-27 Takeda Pharmaceutical Company Limited Sulfonamide derivative and use thereof
US10287305B2 (en) 2016-02-04 2019-05-14 Takeda Pharmaceutical Company Limited Substituted piperidine compound and use thereof
WO2017135306A1 (fr) 2016-02-04 2017-08-10 Takeda Pharmaceutical Company Limited Composé de pipéridine substituée et son utilisation
US20170226137A1 (en) 2016-02-04 2017-08-10 Takeda Pharmaceutical Company Limited Substituted piperidine compound and use thereof
US10508083B2 (en) 2016-02-04 2019-12-17 Takeda Pharmaceutical Company Limited Substituted piperidine compound and use thereof
WO2018164191A1 (fr) 2017-03-08 2018-09-13 武田薬品工業株式会社 Composé de pyrrolidine substituée et son utilisation
WO2018164192A1 (fr) 2017-03-08 2018-09-13 武田薬品工業株式会社 Composé de pyrrolidine substituée et son utilisation
WO2019027058A1 (fr) 2017-08-03 2019-02-07 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
WO2019027003A1 (fr) 2017-08-03 2019-02-07 武田薬品工業株式会社 Composé hétérocyclique et son application
US10428023B2 (en) 2017-08-03 2019-10-01 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHEMELLI R.M. ET AL., CELL, vol. 98, 1999, pages 437 - 451
DEL MAR-GRASA, M. ET AL., OBESITY RESEARCH, vol. 9, 2001, pages 202 - 9
HARRIS ET AL., TRENDS NEUROSCI., vol. 29, no. 10, 2006, pages 571 - 577
OLITVAK, D.A. ET AL., DIG. DIS. SCI., vol. 44, no. 3, 1999, pages 643 - 48
PEPT. SCI., vol. 8, no. 8, August 2002 (2002-08-01), pages 461 - 75
PEYRON ET AL., JOURNAL NEUROSCI., vol. 18, no. 23, 1998, pages 9996 - 100150
SAKURAI T. ET AL., CELL, vol. 92, 1998, pages 573 - 585

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3816154A4 (fr) * 2018-06-29 2022-03-30 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son application
US11655241B2 (en) 2018-06-29 2023-05-23 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US11028048B2 (en) 2019-01-31 2021-06-08 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
EP3923933A4 (fr) * 2019-02-13 2022-08-17 Merck Sharp & Dohme Corp. Agonistes du récepteur de l'orexine de type pyrrolidine
WO2021106975A1 (fr) 2019-11-27 2021-06-03 武田薬品工業株式会社 Composé hétérocyclique
WO2022208478A1 (fr) 2021-04-02 2022-10-06 Takeda Pharmaceutical Company Limited Utilisation d'un agoniste du récepteur de l'orexine 2 pour la récupération post-opératoire
WO2022233872A1 (fr) * 2021-05-03 2022-11-10 Jazz Pharmaceuticals Ireland Limited Agonistes du récepteur de l'orexine et leurs utilisations
WO2022251302A1 (fr) * 2021-05-26 2022-12-01 Alkermes, Inc. Composés macrocycliques bicycliques fusionnés substitués et méthodes de traitement associées
WO2022269049A1 (fr) * 2021-06-25 2022-12-29 Jazz Pharmaceuticals Ireland Limited Agonistes du récepteur de l'orexine à base de sulfonamide et leurs utilisations
WO2023167865A1 (fr) * 2022-03-01 2023-09-07 Orexia Therapeutics Limited Dérivés hétérocycliques bicycliques et utilisations associées
WO2023199091A1 (fr) 2022-04-12 2023-10-19 Takeda Pharmaceutical Company Limited Composé hétérocyclique

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